Method of formulating and designing liquid drug suspensions containing ion exchange resin particles

ABSTRACT

The invention relates to the formulation and quality control of liquid drug suspensions. In particular, the invention relates to methods of formulating liquid suspensions comprising drug-containing resin particles. The invention also relates to methods of confirming the acceptability of drug-containing resin particles for use in formulating liquid drug suspensions. The invention further relates to methods of formulating liquid suspensions in which drug-containing resin particles, the liquid suspension, or both are modified to achieve a desired in vitro dissolution profile. The invention also relates to a novel dissolution method and methods of predicting in vivo bioequivalence based on in vitro dissolution methods.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/292,420, filed Jan. 5, 2010, the disclosure of which is herebyincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

The invention relates to the formulation and quality control of liquiddrug suspensions for oral administration. In particular, the inventionrelates to methods of formulating liquid suspensions comprisingdrug-resin complex particles. The invention also relates to methods ofconfirming the acceptability of drug-resin complex particles for use informulating liquid drug suspensions. The invention further relates tomethods of formulating liquid suspensions in which drug-resin complexparticles, the liquid suspension, or both are modified to achieve adesired in vitro dissolution profile. The invention also relates to anovel dissolution method and methods of predicting in vivobioequivalence based on in vitro dissolution methods.

(b) Description of the Related Art

Sustained Released Liquid Drug Suspensions

Sustained- or prolonged-release dosage forms provide a controlled supplyof drug to an organism over an extended period of time. Oralcontrolled-release drug preparations may provide the convenience ofdaytime dosing where the dosage form can be administered to an animalfirst thing in the morning and provide therapeutic levels of the drugthroughout the day. Further, an oral controlled-release drug preparationmay deliver drugs in a manner that will maintain therapeuticallyeffective plasma levels in an mammal over a period of time that issignificantly longer than that which is given by a typical drug dosageform. This eliminates the need to interrupt sleep to take medication andcan prevent missed doses, thus improving patient compliance. Benefitsobtained from such a controlled release of a specific drug include thecontrol of cough, sleep, enuresis, pain and migraine headaches.Additionally, controlled release of antimicrobials can be used to treator prevent infection.

Liquid oral dosage forms are known in the art. Liquid formulations havethe distinct advantages of dosage flexibility and ease of swallowing.Moreover, there is a recognized need for sustained release formulationsto be available in a convenient, easy-to-take liquid dosage form.However, the formulation of liquid oral suspensions havingsustained-released capabilities has only resulted in limited success. Inpart, this is due to the challenges presented in maintaining thestability of sustained-release particles when present in liquiddispersal systems, and the difficulty in achieving sustained release ofthe drug from the dispersed phase.

Ion-Exchange Drug Resins

Ion-exchange technology has been an approach utilized for achievingsustained release for solid dosage forms and various attempts have beenmade to further utilize the technology in liquid suspension formulationsas well. For example, U.S. Pat. No. 2,990,332 discloses a method ofcontrolling the release rate of drug by adsorbing the salt form of adrug onto a carrier resin such as an ion-exchange resin. However, whilecomplexing drugs on ion-exchange resins has been effective fortaste-masking, such uncoated complexes provide only a relatively shortdelay of drug release and a poor control of drug release, becausecontrol of release rate is limited to variation in particle size andcross-linkage of the sulfonic acid-type resin used to prepare theadsorption compounds.

Another approach to prepare liquid suspensions having sustained-releasedcapabilities is by coating drug resins with a water-permeable diffusionbarrier. For example, U.S. Pat. No. 4,221,778 discloses a method forpreparing products having controlled release properties involving athree-step process: (i) preparation of a drug-resin complex; (ii)treating this complex with a suitable impregnating agent; and (iii)coating the particles of treated complex with a water-permeablediffusion barrier. The impregnation agents are believed to act ashumectants to stabilize the size of the swellable particle or minimizerupturing of the water-permeable diffusion barrier, and the barriercoating is believed to delay the release rate of the drug. U.S. Pat.Nos. 4,996,047 and 5,980,882 also provide drug-ion-exchange resincomplex particles coated with a water-permeable diffusion barrier layer.

U.S. Pat. No. 4,762,709 discloses a formulation wherein a coated firstdrug/ion-exchange resin particle is suspended in a liquid carrier withan uncoated second drug/ion-exchange resin component bearing the samecharge as the first drug in the coated first drug/ion-exchange resinparticle. According to the reference, the release rate of the first drugfrom the coated first drug/ion-exchange resin particle is increased whenthe second drug is present in the second uncoated drug/ion-exchangeresin complex compared to when the second drug is included with thefirst drug in the coated first drug/ion-exchange resin.

A product based on this ion-exchange technology is Tussionex®Pennkinetic® Extended-Release Suspension. Tussionex® drug suspensioncontains hydrocodone polistirex equivalent to 10 mg hydrocodonebitartrate and chlorpheniramine polistirex equivalent to 8 mgchlorpheniramine maleate. Tussionex® drug suspension was approved by theFDA in 1987.

Even though at least one liquid drug ion-exchange system was introducedover 20 years ago, very few products utilizing this technology exist inthe market place. This is possibly due to (i) the poor suitability ofthe ion-exchange resin (i.e., hydrophobicity and swelling); (ii) thecomplex formulation and manufacturing processes that are required; and(iii) long term stability problems.

As such, there is a need in the art to develop sustained release liquiddosage forms and in particular, liquid dosage forms with betterpharmacologic properties and stability that will appeal to thecommercial marketplace. In particular, there remains a need forsustained release liquid dosage forms, suitable for once-a-day ortwice-a-day administration of drugs.

Drug Development and Manufacturing

Drug development and manufacturing involves many processes includingproduct design, product testing, quality control, and final productformulation. These processes are expensive, laborious, andtime-consuming.

As such, there is a need in the art to simplify the processes of drugformulation design and quality control, and it would be useful to reducethe time and cost of performing these processes. In particular, there isalso a need to develop quality control methods that ensure batches areefficiently and effectively reproduced. Likewise, there is a need todevelop suitable methods for monitoring the effects of adjustingparameters in the development of liquid drug suspensions such asmodifying particle size and coating of drug-containing resin particlesand for qualifying drug-containing resin particles.

SUMMARY OF THE PREFERRED EMBODIMENTS OF THE INVENTION

The present invention addresses these needs by providing various methodsof testing liquid drug suspensions and quality control of liquid drugsuspensions. The invention also relates to methods of predicting in vivobioequivalence based on in vitro dissolution methods.

In one embodiment, the invention provides a method of testing a drugsuspension by comparing an in vitro dissolution profile for a testsuspension comprising drug-resin complex particles to a control in vitrodissolution profile to determine whether the test suspension in vitrodissolution profile matches the control in vitro dissolution profile.The in vitro dissolution assay is performed using a test suspensioncomprising drug-resin complex particles to generate a test in vitrodissolution profile, where there is a pre-determined hold period betweenthe formation of the test drug suspension and initiation of thedissolution assay for the test drug suspension. The test in vitrodissolution profile is then compared to a control in vitro dissolutionprofile that correlates to a target in vivo profile, and which generatedby an in vitro dissolution assay for a control drug suspension, wherethere is a similar pre-determined hold period between the formation ofthe control drug suspension and initiation of the dissolution assay forthe control drug suspension. The pre-determined hold period between theformation of the test drug suspension and initiation of the dissolutionassay for the test drug suspension, and the similar pre-determined holdperiod for the control drug suspension are substantially less than aperiod necessary for a drug suspension to fully age, and will beconsidered substantially identical so long as the properties of the drugsuspensions do not change substantially during the time between theshorter and the longer of the two lag periods. Suitable pre-determinedhold periods substantially less than a period necessary for a drugsuspension to fully age may be about or less than 14 days, 13 days, 12days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days,3 days, 2 days, 1 day, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours,or 4 hours.

In an alternative embodiment, the dissolution assay for the test drugsuspension is initiated promptly after the formation of the test drugsuspension, and the dissolution assay for the control drug suspension isinitiated promptly after the formation of the control drug suspension.In a particular embodiment, the dissolution assay of the test drugsuspension and the dissolution assay of the control drug suspension areinitiated after substantially identical lag periods. Lag periods forthis embodiment may be of the same duration as the pre-determined holdperiods described above.

In another embodiment, the drug-resin complex particles may be modifiedif the test suspension in vitro dissolution profile does not match thecontrol in vitro dissolution profile. In a particular embodiment, themethod further comprises modifying the drug-resin complex particles toform modified drug-resin complex particles and combining the modifieddrug-resin complex particles with a plurality of excipients in a liquidcarrier to form a liquid test drug suspension, and comparing an in vitrodissolution profile of this test suspension to a control in vitrodissolution profile. In particular embodiments, the drug-resin complexmay be modified by, for example, increasing the weight of coating on thedrug-resin complex particle, modifying the size of the drug-resincomplex particle, or modify the amount of drug loaded above or below theholding capacity on said drug-resin complex particle to modify the rateof dissolution of the test suspension.

In another embodiment, the test drug suspension may be modified if thetest suspension in vitro dissolution profile does not match the controlin vitro dissolution profile. In a particular embodiment, the methodcomprises modifying the test drug suspension to form a modified testdrug suspension and comparing an in vitro dissolution profile of themodified test suspension to a control in vitro dissolution profile. Inparticular embodiments, the test suspension may be modified, forexample, by altering the ionic strength of the test drug suspension oraltering the active resin-site balance.

In another embodiment, the invention provides a method for confirmingthe acceptability of a quantity of drug-resin complex particles bycomparing an in vitro dissolution profile of a test suspensioncomprising a sample of the quantity of drug-resin complex particles tocontrol in vitro dissolution profile and accepting or rejecting thequantity of drug-resin complex particles based on this comparison.

In another embodiment, the invention provides for a method offormulating a liquid drug suspension comprising suspending drug-containresin particles in a liquid suspension, the drug-containing resinparticles comprising a first plurality of particles comprising awater-permeable coating and a second plurality of uncoated particles,and the first and second plurality of particles containing the samedrug. In a preferred embodiment, the liquid drug suspension provides forearly onset of therapeutic effect, while masking the taste of the drugand maintaining bioequivalence and bioavailability, or efficacy, for anextended period.

In another particular embodiment, the invention provides for an extendedrelease liquid drug suspension that is bioequivalent to Tussionex® drugsuspension. In a preferred embodiment, the liquid drug suspension has atighter particle size distribution and lower batch-to-batch variabilitythan Tussionex® drug suspension.

In yet another embodiment, the invention provides for a method of makinga liquid drug suspension that is bioequivalent to Tussionex® drugsuspension. In one embodiment, the method comprises dispersing xanthangum prior to hydration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a method of obtaining an in vitro dissolution profile ofa liquid drug suspension which correlates with in vivo performance.

FIG. 2 depicts a method of using a prompt dissolution assay to refinedrug-containing resin particles.

FIG. 3 depicts a method of using a prompt dissolution assay to refine aliquid drug suspension.

FIG. 4 shows the amount of drug from chlorpheniramine polistirex andhydrocodone polistirex released in vitro after 90 minutes in various pHbuffers.

FIG. 5 shows an in vitro dissolution profile of chlorpheniraminepolistirex in 0.1 N HCl over time.

FIG. 6 shows an in vivo serum concentration profile of chlorpheniraminepolistirex.

FIG. 7 shows in vitro dissolution profiles for three batches ofethylcellulose coated hydrocodone polistirex resinates using differentcoating levels (low, medium, and high).

FIG. 8 shows in vitro dissolution profiles for hydrocodone coatinglevels that bracket Tussionex®.

FIG. 9 shows in vitro dissolution profiles for two batches of drugproduct comprising coated hydrocodone polistirex resins compared to anin vitro dissolution profile for a Tussionex® drug suspension.

FIG. 10 shows in vitro dissolution profiles for two batches of drugproduct comprising uncoated chlorpheniramine polistirex resins comparedto an in vitro dissolution profile for a Tussionex® drug suspension.

FIG. 11 shows in vivo serum concentration profiles for two batches ofdrug product comprising coated hydrocodone polistirex resins compared toan in vivo serum concentration for a Tussionex® drug suspension.

FIG. 12 shows in vivo serum concentration profiles for two batches ofdrug product comprising uncoated chlorpheniramine polistirex resinscompared to an in vivo serum concentration for a Tussionex® drugsuspension.

FIG. 13 shows an in vitro-in vivo correlation as described in Example 3.

FIG. 14 shows a mathematical model for the plasma absorption of thespecified dosage form of coated hydrocodone polistirex using theWager-Nelson method.

FIG. 15 shows a graphical representation of changes in drug productsrelease profiles over time measured from completion of final suspensionwith a high coating level.

FIG. 16 shows a graphical representation of changes in drug productsrelease profiles over time measured from completion of final suspensionwith a low coating level.

FIG. 17 shows a graphical representation of the equilibrium shift overthe 28 day equilibration period in a suspension of hydrocodonepolistirex resin and chlorpheniramine polistirex resin.

FIG. 18 shows a graphical representation of the equilibrium shift of adrug product that was prepared and stored at 50° C.

FIG. 19 shows a graphical representation of the equilibrium shift of adrug product at different pH levels.

FIG. 20 shows a graphical representation of the equilibrium shift of adrug product that contains hydrocodone polistirex resin, but does notcontain chlorpheniramine polistirex resin.

FIG. 21 shows release profiles of (a) a hydrocodone resin with a highcoating weight when prepared in a drug suspension substantially similarto a final drug suspension (“Suspension—Day 1”), and (b) the hydrocodoneresin by itself (“Raw Material”), tested using the same dissolution testmethods as the finished product, but without first suspending it in adrug suspension.

FIG. 22 shows release profiles of (a) a hydrocodone resin with a lowcoating weight when prepared in a drug suspension substantially similarto a final drug suspension (“Suspension—Day 1”), and (b) the hydrocodoneresin by itself, tested using the same dissolution test methods as thefinished product, but without first suspending it in a drug suspension(“Raw Material”).

FIG. 23 shows a graphical representation of the percent volume of twosamples (i.e., the particle size distribution), as measured using lightscatter diffraction. One sample is commercial Tussionex®; the othersample is a product formulated as described in Example 3.

FIG. 24 shows a graphical representation of the percent volume of eachindividual fraction (i.e., the particle size distribution), as measuredusing light scatter diffraction, for six fractions of a productformulated as described in Example 3.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF INVENTION

Solid drug dosages are generally stable until the drug product isadministered to a patient. On the other hand, liquid drug products aremore likely to undergo chemical reactions during storage periods betweenmanufacture and administration. The present inventors have discoveredthat extended release products, where the drug is sequestered by bindingto an ion exchange material, are particularly susceptible to thisphenomenon. In fact, when using ion exchange resins to ionically bind adrug, any formulations where the ion exchange resin has free sites areinitially likely to be thermodynamically unstable, and if such aformulation is in the form of a liquid suspension, thermodynamics willdrive changes in the amount and location of bound drug during storageuntil the system reaches a thermodynamically stable equilibrium. Duringthe period that the approach to equilibrium is proceeding, the releaseprofile for the drug will change over the time period.

While a liquid drug product typically reaches a stable equilibrium bythe time it is administered to a patient due to the time lagaccompanying distribution after manufacture, the manufacturer is not aslucky as the patient. Changes in the relative amounts of different formsof the drug (e.g., bound/unbound, sequestered behind semi-permeablemembranes, etc.) are likely to occur for some time after manufacture ofa liquid drug suspension. The manufacturer can, of course, suspend anyproduct testing until the product reaches equilibrium. However, thepresent inventors have devised an alternative method to avoid the delayin processing that would be occasioned by a wait for equilibration. Themethods of this invention permit manufacturers who need to obtaininformation about the drug resin complex to assay liquid drugsuspensions promptly after manufacture and still obtain information thatis consistent with the behavior of a completely equilibrated (i.e.,“fully aged”) product.

The invention provides for various methods of formulating oral liquidsuspensions comprising drug-containing ion-exchange resin particles.Methods of formulating such products generally comprise the followingsteps: (a) designing/obtaining drug-containing resin particles; (b)suspending the drug-containing resin particles into a suspensionpreparation; (c) introducing an aliquot of the suspension preparationinto a dissolution medium and producing a test in vitro dissolutionprofile by determining the concentration of drug in the dissolutionmedium; (d) comparing said test in vitro dissolution profile to acontrol in vitro dissolution profile, obtained from a control liquiddrug suspension, that correlates to a target in vivo profile. If thetest in vitro dissolution profile matches the control dissolutionprofile, then the suspension preparation will be suitable for finalformulation. If the test in vitro dissolution profile does not match thecontrol dissolution profile, then the drug-containing resin particles,the suspension preparation, or both may be modified. The suspensionpreparation and/or the control liquid drug suspension may besubstantially similar in physicochemical characteristics to a finallyformulated and fully aged suspension. The invention provides for variousquality control methods using these steps and modifications thereof.

The inventors have observed that a fully aged liquid formulationcomprising drug-containing ion-exchange resin particles can be used todetermine whether the formulation will correspond to a desired in vivoserum concentration profile. In a particular example, the inventorsprepared a liquid formulation comprising drug-containing ion-exchangeresin particles and allowed this formulation to fully age (e.g., held insuspension until thermodynamic stability was reached, approximately onemonth). An in vitro dissolution assay was performed using an aliquot ofthe fully aged suspension. This fully aged suspension was thenadministered to subjects, and it was determined that the suspension wasbioequivalent to an FDA approved drug based on in vivo serumconcentration profiles obtained from the subjects. The inventors thenestablished a in vitro/in vivo correlation (IVIVC) between the in vitrodissolution profile of the fully aged suspension and the in vivo serumconcentration profile, and demonstrated that the in vitro dissolutionprofile of a fully aged suspension can be used to determine whether aliquid formulation will correspond to a desired in vivo serumconcentration profile. A schematic of this process is shown in the topline and right hand side of FIG. 1. It will be understood that the fullyaged suspension used in such studies is preferably substantially similarin physicochemical characteristics to a finally formulated and fullyaged suspension product. As such, the fully aged suspension used in suchstudies need not, for example, include dyes or flavorings.

The inventors then surprisingly discovered that it is not necessary towait for the period required to obtain a fully aged liquid drugformulation before determining whether the formulation will correspondto a desired in vivo serum concentration profile. Indeed, the inventorsdiscovered that during the process of designing or manufacturing aliquid drug formulation, the drug-containing ion-exchange resinparticles and/or the liquid drug suspension can be monitored or testedto ensure quality and/or a desired drug release profile or absorptionprofile without waiting for the liquid drug suspension to fully age. Inparticular, the inventors determined that an in vitro dissolution assaymay be performed on a test suspension promptly after making a liquiddrug formulation. The in vitro dissolution profile obtained from thisprompt assay is then compared to an in vitro dissolution profile of acontrol suspension obtained by a similar prompt assay and which has beencorrelated to a desired in vivo serum concentration profile. (See lefthand side and lower line of FIG. 1). When performing the promptdissolution assays for the test and control suspensions, aliquots of thetest and control suspensions are collected and tested for dissolutionprofiles after the same lag period from completion of the suspension. Ifthe in vitro dissolution profile of the test suspension does not matchthe in vitro dissolution profile of the control suspension, thenmodification of (1) the drug-containing ion-exchange resin particles(see FIG. 2); (2) the liquid drug suspension (see FIG. 3); or (3) bothdrug-containing ion-exchange resin particles and the liquid drugsuspension may be undertaken to achieve the desired in vitro dissolutionprofile.

The inventors observed that a suitable period of time (e.g.,approximately one month) was necessary to achieve a thermodynamicallystable suspension. The inventors observed that after a liquid drugsuspension comprising drug-containing ion-exchange resin particles isformulated, the suspension becomes more stable as time passes until itreaches a thermodynamic stability. The present inventors determined thatin vitro dissolution profiles obtained from time periods substantiallyless than a period necessary for a drug suspension to fully age can becorrelated with an in vitro dissolution profile of a fully aged drugsuspension that, in turn, has been correlated with a desired in vivoserum concentration profile. As such, the inventors have determined thatin vitro dissolution profiles obtained promptly (i.e., from time periodssubstantially less than a period necessary for a drug suspension tofully age) can be predictive of desired in vivo serum concentrationprofiles. This surprising discovery will significantly reduce time andcost for designing liquid drug formulations.

Definitions

As used herein, “finally formulated” means a suspension that includesall of the components typically formulated for commercial distributionsuch as stabilizers, thickeners, dyes, flavorants, etc. As used herein,“substantially similar in physicochemical characteristics” means asuspension having the same colligative and ionic (e.g., pH) properties,viscosity, and specific gravity. These properties may be measured bymethods known in the art.

As used herein, “fully aged” means a liquid suspension that is stable totime-dependent changes in release profiles. As used herein, “a periodnecessary for a drug suspension to fully age” means a time period afterpreparation of a liquid suspension sufficient for the suspension tobecome stable. In particular, for a fully aged suspension, all chemicalforms or states of the drug (e.g., bound/unbound, ionized/unionized, onone side of a semi-permeable membrane or the other, etc.) are inequilibrium with each other. As used herein, “finally formulated andfully aged suspension product” means a product that is suitable forcommercial distribution.

As used herein, “control” drug preparations are pharmaceutically activecompositions which have been shown to be efficacious in vivo,preparations having the same composition as a preparation which hasdemonstrated in vivo efficacy, preparations which have been shown to bebioequivalent to a reference listed drug, or preparations having thesame composition as a preparation which has demonstrated bioequivalenceto a reference listed drug. A control in vitro dissolution profile maybe generated using a control drug preparation or a preparation of thesame drug with substantially similar physico-chemical characteristics tothe control drug preparation.

As used herein, a dissolution profile is “equivalent” to another profileif the f2 similarity factor calculated for the two profiles is greaterthan or equal to 50. (See Moore and Harmer, Pharm. Tech. 20: 64-74,1996). As used herein, two dissolution profiles “match” if they areequivalent or if one falls within pharmaceutically acceptable limits,typically 80% to 125%, of the other, directly, or indirectly through apredetermined mathematical relationship (e.g., using informationcorrelated for different lag times).

As used herein, an “early onset of therapeutic effect” relates tospecified amount of drug released within a shortened timeframe (i.e.,have more Area Under Curve (AUC) initially), but still passes f2testing. For example, the invention contemplates the release of at least15% more of the drug within the first 15, 30, 60, 75, or 90 minutes ofadministration, as compared to conventional oral dosage forms of thesame drug. An “early onset of therapeutic effect” is contrasted with“dose dumping,” which is the premature and exaggerated release of a drugthat produces adverse effects or toxicity.

As used herein, an assay is “prompt” or it is performed “promptly” if itis performed on a newly manufactured suspension before the suspensionreaches equilibrium. An assay may be considered prompt even though thereis a predetermined hold period or lag time between manufacture of asuspension and its assay. In particular, prompt assays are likely to beperformed no more than two weeks after manufacture of a suspension iscompleted, preferably after a lag time of no more than three days, morepreferably no more than 24 hours. Two comparable assays are bothperformed promptly if the lag period between them differs by less than20% or if the properties of the drug suspensions do not changeappreciably in the difference between their lag periods. Predeterminedhold times for such “prompt” assays are considered substantiallyidentical.

Drug-Resin Complex Particles

The invention provides for various methods of product formulation andassays involving drug-containing resin particles. These particlescomprise at least one pharmacologically active drug bound to particlesof an ion-exchange resin to provide a drug-resin complex. Thesedrug-resin complex particles may be coated with a water-permeablediffusion barrier coating that is insoluble in gastrointestinal fluidsthereby providing a controllable sustained release of drug underconditions encountered in the gastrointestinal tract. The particles mayalso include an enteric coating. Drugs are typically bound to the resinparticles by ionic bonds. The drug-resin complex particles may alsocontain unbound drug or drugs bound by non-ionic means.

Resins

Ion-exchange resins suitable for use in the preparations and methodsdescribed herein are water-insoluble and comprise a pharmacologicallyinert organic and/or inorganic matrix containing covalently boundfunctional groups that are ionic or capable of being ionized under theappropriate conditions of pH. The organic matrix may be synthetic (e.g.,polymers or copolymers of acrylic acid, methacrylic acid, sulfonatedstyrene, sulfonated divinylbenzene), or partially synthetic (e.g.,modified cellulose and dextrans). The inorganic matrix preferablycomprises silica gel modified by the addition of ionic groups.Covalently bound ionic groups may be strongly acidic (e.g., sulfonicacid, phosphoric acid), weakly acidic (e.g., carboxylic acid), stronglybasic (e.g., primary amine), weakly basic (e.g. quaternary ammonium), ora combination of acidic and basic groups. In general, the types ofion-exchangers suitable for use in ion-exchange chromatography and forsuch applications as deionization of water are suitable for use in thecontrolled release of drug preparations. Suitable ion exchange resinsare also sold under the trade names Amberlite and Dowex. Suchion-exchangers are described by H. F. Walton in “Principles of IonExchange” (pp. 312-343) and “Techniques and Applications of Ion-ExchangeChromatography” (pp. 344-361) in Chromatography. (E. Heftmann, editor),Van Nostrand Reinhold Company, New York (1975), incorporated herein byreference. Exemplary ion-exchange resins that can be used in the presentinvention have exchange capacities below about 6 milliequivalents(meq)/gram and preferably below about 5.5 meq/gram.

Typically, the size of the ion-exchange particles is from about 30microns to about 500 microns, preferably the particle size is within therange of about 40 micron to about 150 micron for liquid dosage forms,although particles up to about 1,000 micron can be used for solid dosageforms, e.g., tablets and capsules. Particle sizes substantially belowthe lower limit are difficult to handle in all steps of the processing.Commercially-available ion-exchange resins having an irregular shape andlarger diameters up to about 200 micron, are gritty in liquid dosageforms and have a greater tendency to fracture when subjected todrying-hydrating cycles. Moreover, it is believed that the increaseddistance that a displacing ion must travel in its diffusion into theselarge particles, and the increased distance the displaced drug musttravel in its diffusion out of these large particles, cause a measurablebut not readily controlled prolongation of release, even when thedrug-resin complexes are uncoated. Release of drug from uncoateddrug-resin complexes with particle sizes in the approximate range of 40micron to 150 micron is relatively rapid in the appropriate environment.Satisfactory control of the release from such complexes is achievedalmost exclusively by the applied diffusion barrier coating.

Both regularly and irregularly shaped particles may be used as resins.Regularly shaped particles are those particles that substantiallyconform to geometric shapes, such as spherical, elliptical, cylindricaland the like, which are exemplified by Dow XYS-40010.00 and DowXYS-40013.00 (The Dow Chemical Company). Irregularly shaped particlesare all particles not considered to be regularly shaped, such asparticles with amorphous shapes and particles with increased surfaceareas due to surface channels or distortions. Irregularly shapedion-exchange resins of this type are exemplified by Amberlite IRP-69(Rohm and Haas). Two of the preferred resins of this invention areAmberlite IRP-69 and Dow XYS-40010.00. Both are sulfonated polymerscomposed of polystyrene cross-linked with 8% of divinylbenzene, with anion-exchange capacity of about 4.5 to 5.5 meq/g of dry resin (Na⁺-form).Their essential difference is in physical form. Amberlite IRP-69consists of irregularly-shaped particles with a size range of 47 micronto 149 micron produced by milling the parent large-sized spheres ofAmberlite IRP-120. The Dow XYS-40010.00 product consists of sphericalparticles with a size range of 45 micron to 150 micron. Another usefulexchange resin, Dow XYS-40013.00, is a polymer composed of polystyrenecross-linked with 8% of divinylbenzene and functionalized with aquaternary ammonium group; its exchange capacity is normally within therange of approximately 3 to 4 meq/g of dry resin.

The following U.S. Patents and Publications describe resins suitable foruse in the preparations and methods described herein: U.S. Pat. Nos.4,221,778; 4,996,047; and 5,980,882; U.S. Publication Nos. 2003/0099711;2006/0193877; 2007/0059270; 2007/01400983; 2007/0148239; and2009/0011027. The disclosure of each of these patents and publicationsis incorporated by reference herein in their entireties.

As described herein, one of skill in the art may modify the resinparticle size to modify a drug release profile and ultimately achieve adesired in vivo serum concentration profile.

Drugs

Drugs that are suitable for use in these preparations include drugs forthe treatment of respiratory tract disorders such as, for example,antitussive expectorants such as dihydrocodeine phosphate, codeinephosphate, noscapine hydrochloride, phenylpropanolamine hydrochloride,potassium guaiacolsulfonate, cloperastine fendizoate, dextromethorphanhydrobromide and chloperastine hydrochloride; bronchodilators such asdl-methylephedrine hydrochloride and dl-methylephedrine saccharinate;and antihistamines such as fexofenadine HCl or di-chlorpheniraminemaleate. Other drugs useful for the invention include drugs for thetreatment of digestive tract disorders such as, for example, digestivetract antispasmodics including scopolamine hydrobromide, metixenehydrochloride and dicyclomine hydrochloride, drugs for the treatment ofcentral nervous system disorders such as, for example, antipsychoticdrugs including phenothiazine derivatives (chlorpromazine hydrochloride,etc.) and phenothiazine-like compounds (chlorprothixene hydrochloride,etc.), antianxiety drugs such as benzodiazepine derivatives(chlordiazepoxide hydrochloride, diazepam, etc.), antidepressants suchas imipramine compounds (imipramine hydrochloride, etc.), antipyreticanalgesics such as sodium salicylate, and hypnotics such asphenobarbital sodium; opioid analgesic drugs such as alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, cyclazocine,desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethotheptazine,ethylmethylthiambutene, ethylmorphine; etonitazene fentanyl, heroin,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levallorphan, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium and compoundscontained therein, oxycodone, oxymorphone, papavreturn, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tramadol, tilidine, salts thereof, mixtures ofany of the foregoing, mixed mu-agonists/antagonists, mu-antagonistcombinations, and the like; and drugs for the treatment of respiratorysystem disorders such as, for example, coronary dilators includingetafenone hydrochloride, antiarrhythmics such as procainamidehydrochloride, calcium antagonists such as verapamil hydrochloride,hypotensive drugs such as hydrazine hydrochloride, propranololhydrochloride and clonidine hydrochloride, and peripheralvasodilators/vasoconstrictors such as tolazoline hydrochloride.Antibiotics may also be useful such macrolides such as oleandomycinphosphate, tetracyclines such as tetracycline hydrochloride,streptomycins such as fradiomycin sulfate, and penicillin drugs such asdicloxacillin sodium, pivmecillinam hydrochloride andcarbenicillinindanyl sodium. Chemotherapeutic drugs may also be usedincluding sulfa drugs such as sulfisomidine sodium; antituberculosisdrugs such as kanamycin sulfate, and antiprotozoan drugs such asamodiaquine hydrochloride. An excellent sustained releasing effect isobtained in basic drugs for the respiratory tract such as dihydrocodeinephosphate, di-methyl-ephedrine hydrochloride and phenylpropanolaminehydrochloride. The following U.S. Patents and Publications describedrugs suitable for use in the preparations and methods described herein:U.S. Pat. Nos. 4,221,778; 4,996,047; and 5,980,882; U.S. PublicationNos. 2003/0099711; 2006/0193877; 2007/0059270; 2007/01400983;2007/0148239; and 2009/0011027. The disclosure of each of these patentsand publications is incorporated by reference herein in theirentireties.

Alternatively, drugs that are suitable for the invention may be acidic,basic or amphoteric. Acidic drugs that can be used in the presentinvention include, for example, dehydrocholic acid, diflunisal,ethacrynic acid, fenoprofen, furosemide, gemfibrozil, ibuprofen,naproxen, phenytoin, probenecid, sulindac, theophylline, salicylic acidand acetylsalicylic acid. Basic drugs that can be used in the presentinvention include, for example, acetophenazine, amitriptyline,amphetamine, benztropine, biperiden, bromodiphenhydramine,brompheniramine, carbinoxamine, chloperastine, chlorcyclizine,chlorpheniramine, chlorphenoxamine, chlorpromazine, clemastine,clomiphene, clonidine, codeine, cyclizine, cyclobenzaprine,cyproheptadine, desipramine, dexbrompheniramine, dexchlorpheniramine,dextroamphetamine, dextromethorphan, dicyclomine, diphemanil,diphenhydramine, doxepin, doxylamine, ergotamine, fluphenazine,haloperidol, hydrocodone, hydroxychloroquine, hydroxyzine, hyoscyamine,imipramine, levopropoxyphene, maprotiline, meclizine, mepenzolate,meperidine, mephentermine, mesoridazine, methadone, methylephedrine,methdilazine, methscopolamine, methysergide, metoprolol, nortriptylene,noscapine, nylindrin, orphenadrine, papaverine, pentazocine,phendimetrazine, phentermine, phenylpropanolamine, pyrilamine,tripelennamine, triprolidine, promazine, propoxyphene, pro panolol,pseudoephedrine, pyrilamine, quinidine, scopolamine, dextromethorphan,chlorphenitarraizae and codeine. Amphoteric drugs that can be used inthe present invention include, for example, aminocaproic acid,aminosalicylic acid, hydromorphone, isoxsuprine, levorphanol, melphalan,morphine, nalidixic acid, and paraaminosalicylic acid.

Preferably, drugs which may be used in the invention include drugs forthe indication of attention-deficit/hyperactivity disorder (ADHD) suchas methylphenidate, amphetamine and dextroamphetamine,dexmethylphenidate, and clonidine; drugs for the indication ofgastroesophageal reflux disease (GERD) such as ranitidine hydrochloride,omeprazole, lansoprazole, raberprazole sodium; drugs for the indicationof bacterial infections such as tetracylcine, clindamycin,erythrornycine ethylsuccinate, sulfamethoxazole and trimethoprim,clarithromycin, ciprofloxacin; drugs for the indication of chickenpoxsuch as acylovir; drugs for the indication of allergic rhinitis such asfexofenadine and fexofenadine/pseudoephedrine; drugs for the indicationof antitussive/antihistimine such as hydrocodone-chlorpheniramine andcodeine-chlorpheniramine; drugs for the indication of antitussives suchas promethazine, promethazine with codeine, promethazine withdextromethorphan, benzonatate, potassium guaiacol sulfonate,hydrocodone-homatropine, hydrocodone-guaifenesin,codeine-pseudoephedrine, and codeine-guaifenesin; drugs for theindication of epilepsy such as levetiracetam, gabapentin, carbamazepine,topiramate, and baciofen; drugs for the indication of epilepsy/biolarsuch as lamotrigine and valproate sodium; drugs for the indication ofAlzheimer's such as galantamine hydrobromide, rivastigrnine tartrate,and donepezil hydrochloride; drugs for the indication of multiplesclerosis such as tizanadine; drugs for the indication of Parkinson'ssuch as carbidopa-levodopa, ropinirole hydrochloride, and pramipexoledihydrochloride; drugs for the indication of bipolar disorder such asquetiapine fumarate, lithium carbonate, and perphenazine; drugs for theindication of anxiety such as hydroxyzine; drugs for the indication ofdepression such as venlafaxine hydrochloride; drugs for the indicationof moderate/severe pain such as morphine (sulfate), oxycodone,oxycodone/acetaminaphen, hydroorphone, tramadol hydrochloride,hydrocodone/acetaminaphen, and codeine; drugs for the indication oftrigeminal neuralgia such as carbamazepine; and drugs for the indicationof muscle spasms such as cyclobenzapine.

The compositions of this invention may optionally contain one or moreother known therapeutic agents, particularly those commonly utilized incough/cold preparations, such as, for example, a decongestant such aspseudoephedrine hydrochloride, phenylpropanolamine HCl, phenylephrinehydrochloride and ephedrine hydrochloride; an analgesic such asacetaminophen and ibuprofen; an expectorant or mucolytic such asglyceryl guaiacolate, terpin hydrate, ammonium chloride,N-acetylcysteine and ambroxol; an antihistamine such as chlorpheniraminemaleate, doxylamine succinate, brompheniramine maleate anddiphenhydramine hydrochloride; an antitussive such as promethazine,promethazine with codeine, promethazine with dextromethorphan,benzonatate, hydrocodone-homatropine, hydrocodone-guaifenesin,codeine-pseudoephedrine, and codeine-guaifenesin; and anantitussive/antihistimine such as hydrocodone-chlorpheniramine andcodeine-chlorpheniramine. See, e.g., U.S. Pat. No. 4,619,934, which isincorporated by reference herein. Also useful are bronchodilators suchas theophylline and albuterol.

Drug-Resin Complexes

Binding of drug to resin can be accomplished using methods known in theart. Indeed, one of ordinary skill in the art can easily determine theappropriate method depending upon the drug. Typically four generalreactions are used for a basic drug, these are: (a) resin (Na⁺-form)plus drug (salt form); (b) resin (Na⁺-form) plus drug (as free base);(e) resin (H⁺-form) plus drug (salt form); and (d) resin (H⁺-form) plusdrug (as free base). All of these reactions except (d) have cationicby-products and these by-products, by competing with the cationic drugfor binding sites on the resin, reduce the amount of drug bound atequilibrium. For basic drugs, stoichiometric binding of drug to resin isaccomplished only through reaction (d). Without being limited by theory,it is believed that the extent of drug binding is critical to themaintenance of the integrity of the diffusion barrier coating.

Four analogous binding reactions can be carried out for binding anacidic drug to an anion exchange resin. These are: (a) resin (Cl⁻-form)plus drug (salt form); (b) resin (Cl⁻-form) plus drug (as free acid);(c) resin (OH⁻-form) plus drug (salt form); and (d) resin (OH⁻-form)plus drug (as free acid). All of these reactions except (d) have ionicby-products and the anions generated when the reactions occur competewith the anionic drug for binding sites on the resin with the resultthat reduced levels of drug are bound at equilibrium. For acidic drugs,stoichiometric binding of drug to resin is accomplished only throughreaction (d). The binding may be performed, for example, as a batch orcolumn process, as is known in the art. The drug-resin complexes may beprepared by a batch process that is based on reaction (d). Thedrug-resin complex thus formed is collected by filtration and washedwith deionized or purified water to ensure removal of any unbound drug.The complexes are usually air-dried in trays at from 25 to 60° C.

Drug-resin complexes rapidly release the drug in the patient, such as,for example, in the gastrointestinal tract. For example, an AmberliteIR-120 phenylpropanolamine complex with a 35 percent drug loadingreleased 61 percent of the drug in 60 minutes in a 0.1 N hydrochloricacid dissolution medium.

The amount of drug that can be loaded onto a resin will typically rangefrom about 1% to about 80%, preferably about 15% to about 60%, by weightof the loaded drug-resin particles. A skilled artisan with little or noexperimentation can readily determine the optimum loading for any drugresin complex. In a preferred embodiment, loadings of about 30% to about60% by weight of the drug-resin particles can be employed.

The following U.S. Patents and Publications describe drug-resincomplexes suitable for use in the preparations and methods describedherein: U.S. Pat. Nos. 4,221,778; 4,996,047; and 5,980,882; U.S.Publication Nos. 2003/0099711; 2006/0193877; 2007/0059270;2007/01400983; 2007/0148239; and 2009/0011027. The disclosure of each ofthese patents and publications is incorporated by reference herein intheir entireties.

As described herein, one of skill in the art may increase or decreasethe amount of drug loaded on a resin particle to modify a drug releaseprofile and ultimately achieve a desired in vivo serum concentrationprofile.

Impregnation

Drug-resin particles can be impregnated with a humectant substantiallyas described in U.S. Pat. No. 4,221,778. The humectant can be added asan ingredient in the resin drug cornplexation step or preferably, theparticles can be treated with the humectant after complexing. Thistreatment helps particles retain their geometry, and enables theeffective application of diffusion barrier coatings to such particles.One preferred humectant is polyethylene glycol, a hydrophilic agent.Other effective humectant agents include, for example, propylene glycol,lactose, methylcellulose, hydroxypropylmethylcellulose, sugar alcoholssuch as sorbitol, mannitol, polyvinylpyrrolidone, carboxypolymethylene,xanthan gum, propylene glycol, alginate and combinations of theseagents. The humectant may be added in an amount of up to about 50 partsby weight of the resin or 50 to 150 parts by weight of the resin; suchhumectant levels have been found to be effective. Preferably, thehumectant (solvating agent) is added in an amount of about 75 to about100 parts by weight of resin. Such pretreatment of drug-resin complexenables the effective use of diffusion barrier coatings, resulting inthe ability to effectively prolong the release of drugs from drug-resincomplexes.

Diffusion Barrier Coating

Next, loaded particles may be coated with a diffusion barrier comprisinga water-permeable, film-forming polymer. Any coating procedure whichprovides a contiguous coating on each particle of drug-resin complexwithout significant agglomeration of particles may be used. Coatings maybe applied with a fluid-bed coating apparatus having the Wursterconfiguration. Measurements of particle size distribution can be donebefore and after coating to show that agglomeration of particles isinsignificant.

The polymer may be any of a large number of natural or syntheticfilm-formers used singly, or in admixture with each other, andoptionally in admixture with plasticizers, pigments and other substancesto alter the characteristics of the coating. In general, the coatingshould be insoluble in and permeable to water. The water-permeablebarrier comprises a pharmaceutically acceptable polymer such as, forexample, ethylcellulose, methylcellulose, hydroxypropylmethylcellulose(HPMC), hydroxyethlycellulose (HEC), acrylic acid ester, celluloseacetate phthalate, HEC phthalate, HPMC phthalate or other cellulosicpolymers, or mixtures of polymers. Additional examples of coatingpolymers are described by R. C. Rowe in Materials. Used inPharmaceutical Formulation (A. T. Florence, editor), BlackwellScientific Publications, Oxford, 1-36 (1984), incorporated by referenceherein. Preferably the diffusion barrier is ethyl cellulose, forexample, an ethyl cellulose having the content of ethoxyl group from 44to 47.5%, preferably from 45 to 46.5%. In embodiments of the presentinvention, the inclusion of an effective amount of a plasticizer in theaqueous dispersion of hydrophobic polymer will further improve thephysical properties of the film. For example, because ethylcellulose hasa relatively high glass transition temperature and does not formflexible films under normal coating conditions, it is necessary toplasticizer the ethylcellulose before using the same as a coatingmaterial. Generally, the amount of plasticizer included in a coatingsolution is based on the concentration of the film-former, e.g., mostoften from about 1 to about 50 percent by weight of the film-former.Concentration of the plasticizer, however, can only be properlydetermined after careful experimentation with the particular coatingsolution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such a dibutyl sebacate, diethyl phthalate,tributyl citrate and triacetin, although it is possible that otherwater-insoluble plasticizers (such as acetylated monoglycerides,phthalate esters, castor oil, etc.), or water-soluble plasticizers maybe used. A plasticizer such as Durkex 500 vegetable oil may also beincorporated to improve the film forming property. In one alternative,it is desirable to incorporate a water-soluble substance, such as methylcellulose, to alter the permeability of the coating.

One commercially available aqueous dispersion of ethylcellulose isAquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is typicallyprepared by dissolving the ethylcellulose in a water-immiscible organicsolvent and then emulsifying the same in water in the presence of asurfactant and a stabilizer. After homogenization to generate submicrondroplets, the organic solvent is evaporated under vacuum to form apseudolatex. The plasticizer is not incorporated in the pseudolatexduring the manufacturing phase. Thus, prior to using the same as acoating, it is preferable to intimately mix the Aquacoat® with asuitable plasticizer prior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product istypically prepared by incorporating plasticizer into the dispersionduring the manufacturing process. A hot melt of a polymer, plasticizer(e.g., dibutyl sebacate), and stabilizer (e.g., oleic acid) may beprepared as a homogeneous mixture, which is then diluted with analkaline solution to obtain an aqueous dispersion which can be applieddirectly onto substrates.

Another alternative coating material is a mixture of an insoluble filmforming polymer and a water soluble pore former or polymer. Onepreferred water soluble polymer is methyl cellulose.

The barrier coating materials can be applied as an aqueous suspension.Optimum coat weight and coat thickness may be determined for eachdrug-resin complex and generally depend on the drug releasecharacteristics of the resin for a particular drug. For example, fordrug release times within about 1 hour to about 4 hours, the drug-resincomplex may be coated with a light coat weight. A light coat weight is acoat weight present in the amount of about 10% to about 20% by weight ofthe dry resin. For drug release times from about 6 hours to 10 hours, amedium coat weight may be used, i.e. a coat weight present in the amountof 30% to about 35% by weight. For drug release times for about 12hours, a heavy coat weight may be used, i.e. a coat weight of about 40%to 50% by weight of the dry resin. Typically, the water-permeable,film-forming polymer comprises from about 1% to about 60% by weight ofthe drug-resin complex, and preferably from about 20% to about 50% byweight of the dry resin. In terms of coat thickness, preferably, thediffusion barrier coat thickness is at least 5 microns and morepreferably, the diffusion barrier coat thickness is from about 10microns to about 50 microns.

The following U.S. Patents and Publications describe coating materialssuitable for use in the preparations and methods described herein: U.S.Pat. Nos. 4,221,778; 4,996,047; and 5,980,882; U.S. Publication Nos.2003/0099711; 2006/0193877; 2007/0059270; 2007/01400983; 2007/0148239;and 2009/0011027. The disclosure of each of these patents andpublications is incorporated by reference herein in their entireties.

As described herein, one of skill in the art may increase or decreasethe amount of coating, or change the composition of the coating, appliedto a resin particle to modify a drug release profile and ultimatelyachieve a desired in vivo serum concentration profile.

Liquid Drug Suspensions

Liquid oral dosage forms include aqueous and nonaqueous solutions,emulsions, suspensions, and solutions and/or suspensions reconstitutedfrom non-effervescent granules, containing suitable solvents,preservatives, emulsifying agents, suspending agents, diluents,sweeteners, coloring agents, and flavoring agents. Liquid forms, such assyrups and suspensions, preferably contain from about 1% to about 50%,and more preferably from about 1% to about 25%, and most preferably fromabout 3% to about 10%, of the drug-resin complex. Other optionalingredients well known to the pharmacist's art may also be included inamounts generally known for these ingredients, for example, natural orartificial sweeteners, flavoring agents, colorants and the like toprovide a palatable and pleasant looking final product; acidulants, forexample, citric acid, ascorbic acid, or malic acid and the like toadjust pH; antioxidants, for example, butylated hydroxy anisole orbutylated hydroxy toluene; and preservatives, for example, methyl orpropyl paraben or sodium benzoate, to prolong and enhance shelf life.

In preparing the liquid oral dosage forms, the coated drug-resincomplexes are incorporated into an aqueous-based orally acceptablepharmaceutical carrier consistent with conventional pharmaceuticalpractices. An “aqueous-based orally acceptable pharmaceutical carrier”is one wherein the entire or predominant solvent content is water.Typical carriers include simple aqueous solutions, syrups, dispersionsand suspensions, and aqueous based emulsions such as the oil-in-watertype. Preferably, the carrier is a suspension of the pharmaceuticalcomposition in an aqueous vehicle containing a suitable suspendingagent. Suitable suspending agents include Avicel RC-591 (amicrocrystalline cellulose/sodium carboxymethyl cellulose mixtureavailable from FMC), guar gum and the like. Such suspending agents arewell known to those skilled in the art. While the amount of water in thecompositions of this invention can vary over quite a wide rangedepending upon the total weight and volume of the drug-resin complex andother optional non-active ingredients, the total water content, based onthe weight of the final composition, will generally range from about 20to about 75%, and, preferably, from about 20 to about 40%, byweight/volume.

Although water itself may make up the entire carrier, typical liquidformulations may contain a co-solvent, for example, propylene glycol,glycerin, sorbitol solution and the like, to assist solubilization andincorporation of water-insoluble ingredients, such as flavoring oils andthe like, into the composition. In general, therefore, the compositionsof this invention preferably contain from about 5 to about 25volume/volume percent and, most preferably, from about 10 to about 20volume/volume percent, of the co-solvent.

As used herein, unless otherwise defined, the term “substantially freeof organic solvent” means that the composition has less than 5% byweight of organic solvents, preferably, less than 2% by weight of thecomposition. More preferably, the term “substantially free of organicsolvent” means that the composition has less than 1% by weight oforganic solvents. Organic solvents include, but are not limited to,chloroform, methylene chloride, acetone, tetrahyrdrofuran, and the like.

Specific Gravity

Any of the methods described herein may include the step of altering thespecific gravity of the liquid drug suspension. Methods of altering thespecific gravity of a liquid suspension are known in the art. Forexample, U.S. Publication No. 2009/0176884, which is incorporated byreference herein in its entirety, describes a method of preparing liquidsuspensions comprising suspending at least one pharmaceutically activecompound in a suspending system (e.g., based on a thixotropic system)and matching/equilibrating the true density of the resin containing atleast one pharmaceutical active with the specific gravity of the aqueousmedium via a density adjusting agent. Accordingly, any of the methodsdescribed herein may further comprise a step of suspendingdrug-containing resin particles in a suspending system to alter thespecific gravity of the liquid drug suspension.

The liquid drug suspension may be manufactured using techniques known inthe art such as those described in U.S. Publication No. 2006/0193877,which is hereby incorporated by reference in its entirety. Moreover, asdescribed herein, one of skill in the art may modify the drug suspensionto modify a drug release profile and ultimately achieve a desired invivo serum concentration profile.

Methods for Predicting In Vivo Performance

The invention provides for a method of obtaining in vim) drug releaseinformation for a liquid drug suspension which is predictive of in vivoperformance. In one embodiment, the method comprises (a) suspendingdrug-containing resin particles in a liquid suspension preparation; (b)obtaining an in vitro dissolution profile of a test sample obtained fromthe suspension preparation of (a); and (c) correlating the in vitrodissolution profile of the test suspension to a desired in vivo serumconcentration profile observed in a subject who has been administered afinally formulated and fully stabilized (aged) suspension product. Thecorrelation to the desired in vivo profile may well be accomplished bycomparison to the in vitro dissolution profile of a fully agedsuspension having an IVIVC to the desired in vivo profile.Alternatively, the test suspension profile may be obtained before fullaging of the test suspension and the correlation may involve comparingthe test suspension profile to a control dissolution profile for thesuspension that produced the IVIVC, but obtained for a sample pulledfrom the suspension at the same delay after production of the suspensionbut before full aging as the sample of the test suspension was pulled.Typically, the liquid suspension preparation in step (a) will besubstantially similar in physicochemical characteristics to a finallyformulated and fully aged suspension. The control dissolution profilemay also be determined for a suspension substantially similar inphysicochemical characteristics to a finally formulated and fully agedsuspension.

This invention is particularly adapted to suspensions which, asmanufactured, comprise elements that are likely to lead todisequilibrium. For example, the suspension ay comprise drugs havingdifferent binding affinities or binding constants, or ion-exchangeresins having different affinities. In another mode, the suspension maycontain both ionically-bound and unbound drug. In yet another mode, thesuspension may comprise partially loaded resins, free resins, resinsites without bound drug. In still another mode, the pH of suspensionmay change over time. In a preferred embodiment, the suspensioncomprises two different drugs. In a more preferred embodiment, the drugsare chlorpheniramine and hydrocodone.

Sampling for Predictive Assays

One can predict whether the test liquid drug suspension will have an invivo serum profile like the control by comparing the in vitrodissolution profile for the liquid drug suspension obtained as describedabove to a control in vitro dissolution profile obtained by performingthe same in vitro dissolution assay on a control liquid drug suspensionhaving a desired in vivo serum concentration profile. Typically, thedesired in vivo serum concentration profile is one that is observed in asubject who has been administered a finally formulated and fully agedsuspension product.

The sample liquid drug suspension may be a suspension as describedherein. An aliquot of the sample liquid drug suspension may be tested byintroducing it into dissolution medium. The aliquot may be removed fromthe test suspension at any time after the suspension is prepared. In onemode, the aliquot may be taken after a period necessary for a drugsuspension to fully age (i.e., after equilibrium is reached betweenvarious forms of a particular drug in the suspension). The aliquot mayalso be taken after a pre-determined hold period, wherein thepre-determined hold is substantially less than the period necessary fora drug suspension to fully age. Suitable hold periods include four hoursafter the suspension is completely manufactured, or 16 hours aftercompletion of manufacture, or one, two, four or five days or one to twoweeks. In any case, the aliquot of the sample is placed into thedissolution medium as soon as practical after it is removed.

Methods for Obtaining a Dissolution Profile for a Liquid Drug Suspension

When formulating a liquid drug suspension for therapy, it is importantto measure in vitro drug release as a function of time (i.e., adissolution profile) for various reasons such as quality control andgenerating data to support in vivo bioavailability. The in vitrodissolution assay according to this invention is an assay which producessuch a profile. In particular, the in vitro dissolution assay may be anassay described herein or any similar assay known in the art.

This invention provides for methods of obtaining in vitro dissolutionprofiles for liquid drug suspensions. The in vitro dissolution protocolmay be an assay that comprises two or more medium conditions, beginningwith an acidic pH (e.g., less than pH 2.0) for a certain period of timeand which is subsequently raised to an acid-to-neutral pH (e.g., abovepH 6.0). Alternatively, the in vitro dissolution may be an assay thatcomprises an acidic pH (e.g., simulated gastric fluid) for a certainperiod of time.

In one embodiment, the method comprises (a) introducing an aliquot of asample liquid drug suspension into a dissolution medium which initiallyhas a pH less than 2.0; (b) adjusting the pH to above 6.0, preferablyabove 6.5, and more preferably about 6.8 about 2 hours after initiationof the assay; and (c) producing an in vitro dissolution profile for theliquid drug suspension by determining the concentration of drug in thedissolution medium at a series of time points after the introduction ofthe drug containing aliquot into the dissolution medium. In a particularembodiment, the method comprises (a) introducing an aliquot of a sampleliquid drug suspension into a dissolution medium which initially has apH less than 2.0; (b) adjusting the pH to between 5.6 and 6.3 about 1hour after initiation of the assay; (c) adjusting the pH to above 6.5,preferably about 6.8 about 2 hours after initiation of the assay; and(d) producing an in vitro dissolution profile for the liquid drugsuspension by determining the concentration of drug in the dissolutionmedium at a series of time points after the introduction of the druginto the dissolution medium.

In another embodiment, the method comprises

(a) introducing an aliquot of a sample liquid drug suspension into adissolution medium, where the dissolution medium contains about 900 mLof 0.1 N HCl;

(b) adding a buffered basic solution equal to about 1/10 the volume ofthe dissolution medium about one hour after the introduction to bringthe pH to between 5.6 and 6.3;

(c) adding a buffered basic solution equal to about 1-10% of the volumeof the dissolution medium after about two hours from the introduction tobring to pH above 6.5;

(d) producing an in vitro dissolution profile for the liquid drugsuspension by determining the concentration of drug in the dissolutionmedium at a series of time points after the introduction of the aliquotinto the dissolution medium.

In another embodiment, the method comprises introducing an aliquot of asample liquid drug suspension into a dissolution medium which mimicsgastric fluid comprising 0.1N HCl with 0.3% (w/v) sodium dodecyl sulfate(also known as sodium lauryl sulfate). In a particular embodiment, thisdissolution assay is performed using a liquid drug suspension comprisingchlorpheniramine. In another embodiment, the method comprisesintroducing an aliquot of a sample liquid drug suspension into adissolution medium comprising simulated gastric fluid TS with 0.20%(w/v) sodium dodecyl sulfate (also known as sodium lauryl sulfate). In aparticular embodiment, this dissolution assay is performed using aliquid drug suspension comprising hydrocodone.

Various methods of adjusting pH are known in the art and may be usedherein. For example, the pH may be modified by steps which involveadding pre-determined amounts of particular reagents (e.g., a potassiumphosphate/sodium hydroxide solution) at set times. (See also U.S. Pat.No. 5,980,882, which is incorporated by reference herein in itsentirety). The invention contemplates that for any of the methods ofobtaining a dissolution profile described herein, these methods may beperformed using a USP Type II (paddle) apparatus and agitating thesolution at 100 rpm. The sample may preferably be agitated at 100 rpm inview of the high viscosity of liquid drug suspensions. The inventorsdetermined that typical paddle speeds of 25/75 rpm may not dispersesuspension matrices that accumulated at the base of the dissolutionvessel. This could cause a “cone effect” that essentially keeps thecoated resin particles from being distributed throughout the vessel andinitiating their release characteristics, at least early in thedissolution time course. (Contrast FDA website on the world wide web ataccessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm,for protocol of dextromethorphan polistirex.)

Methods of Obtaining an In Vitro/In Vivo Correlation

These methods may also include the steps of producing an in vitrodissolution profile of the liquid drug suspension and comparing this invitro dissolution profile to a control in vitro dissolution profileobtained by performing an in vitro dissolution assay on a control liquiddrug suspension as described herein. The dissolution profile may beobtained by determining the concentration of drug in any of thedissolution media described herein.

The inventors have discovered that an in vitro dissolution profileobtained using a GI model provides better correlation to in vivo releasethan simulated gastric fluid alone. In a preferred embodiment, thedissolution profile has a “Level A correlation.” This is apoint-to-point correlation that directly relates to the in vitro and invivo data. Level A models compare the fraction of the drug absorbed inthe body, as is measured by plasma data, directly to the rate ofdissolution in an in vivo setting. The percent of drug absorbed iscalculated by model dependent techniques such as the Wagner-Nelsonprocedure or Loo-Riegelman method or by independent numericaldeconvolution. The relationship is usually linear, although that is notalways the case, as described herein with coated Hydrocodone (HCB)Polistirex (See. Example 3 below), and can serve as an alternative to invivo studies. Nonetheless, due to the strong mathematical relationshipbetween the in vitro and in vivo data in Level A correlation studies,minor changes in the formulation, method of manufacture, and even amountof active can be adjusted without the need for further human clinicaltrials. The in vitro dissolution profile obtained in this method, andthe methods described herein may be predictive of bioequivalence.

Methods of Preparing Suspensions with Desired Release Profiles

The invention also provides for a method of formulating liquid drugsuspensions. In one embodiment, the invention provides for a method offormulating a liquid drug suspension comprising suspending drug-containresin particles in a liquid suspension, wherein the drug-containingresin particles comprise a first plurality of particles comprising awater-permeable coating and a second plurality of uncoated particles,and wherein the first and second plurality of particles contain the samedrug.

Methods for Qualifying Drug-Containing Resin Particles

In order to formulate a liquid drug suspension using drug-containingresin particles, it is necessary to confirm that the particles aresuitable for its intended use. Indeed, the initial particles are testedto confirm that the particles meet a specified criteria and thus willensure reproducibility of the final suspension from batch to batch. Theinvention provides for methods of qualifying drug-containing resinparticles. These methods permit the inspection of incoming materials,facilitate the correction of in-process errors, and reduce costs ofmanufacturing.

In one embodiment, the invention provides a method for confirming theacceptability of a quantity of drug-containing resin particles to beformulated into a suspension product without waiting for the finalproduct batch to be formulated and fully aged. In a preferredembodiment, this method comprises

(a) suspending a quantity of drug-containing resin particles to providea test suspension, wherein the test suspension is substantially similarin physicochemical characteristics to a final drug suspension product;

(b) introducing an aliquot of the test suspension into a dissolutionmedium after a pre-determined hold period from the end of the suspendingstep, the pre-determined hold period being substantially less than aperiod necessary for a drug suspension to fully age;

(c) producing a test suspension in vitro dissolution profile bydetermining the concentration of drug in the dissolution medium at aseries of time points after the introduction of the aliquot;

(d) comparing said test suspension in vitro dissolution profile to acontrol in vitro dissolution profile obtained by performing an in vitrodissolution assay on a control liquid drug suspension, wherein thecontrol in vitro dissolution assay is performed after the samepre-determined hold period, which is substantially less than the periodnecessary for a drug suspension to fully age; and

(e) accepting or rejecting said quantity of drug-containing resinparticles based on the comparison in step (d). A suitable control liquiddrug suspension would be one having a desired in vivo serumconcentration profile observed in a subject who has been administered afinally formulated and fully aged suspension product.

These methods may also include the steps of producing an in vitrodissolution profile of the liquid drug suspension and comparing this innitro dissolution profile to a control in vitro dissolution profileobtained by performing an in vitro dissolution assay on a control liquiddrug suspension as described herein. The dissolution profile may beobtained by determining the concentration of drug in any of thedissolution media described herein.

The invention provides that the drug-containing resin particles areaccepted if the test suspension in vitro dissolution profile isequivalent to the control in vitro dissolution profile. If the particlesdo not meet the specified criteria, then the particles may be modifiedas described herein.

The pre-determined hold period may be any time period so long as thepre-determined hold period is substantially less than a period necessaryfor a drug suspension to fully age. For example, the pre-determined holdperiod may be any period long enough after completion of the suspensionof the drug-containing resin particles to permit reproducible samplingof the drug suspension from batch-to-batch, such as 10 minutes, butpreferably at least 4 hours, optionally at least 20, 24, or 48 hours, ora similar period which can be shown to produce an in vitro dissolutionprofile which is predictably consistent with the profile of the fullyaged suspension product. Also, the pre-determined hold period must beconstant from liquid suspension to liquid suspension (i.e., batch tobatch) to ensure reproducibility.

The dissolution medium may comprise any of the dissolution mediadescribed herein. For example, the dissolution medium may initially havea pH less than 2.0, and then be adjusted to have a pH above 6.0,preferably above 6.5, and more preferably about 6.8 after about 2 hours.

In a typical embodiment, the test suspension has a compositionsubstantially equivalent in physico-chemical characteristics to anintended final formulation. The test suspension may have the sameingredients as a final drug suspension. Preferably, the test suspensionhas the same ingredients as a final drug suspension except that the testsuspension may not contain coloring agents, flavoring agents,preservatives, non-ionic suspending agents, surfactants, or combinationsthereof.

The quantity of drug-containing resin particles may comprise a firstplurality of particles comprising a first drug and a second plurality ofparticles comprising a second drug. The first plurality of particles mayfurther comprise a water-permeable coating, and the second plurality ofparticles may omit the water-permeable coating (i.e., the particle isuncoated). Alternatively, the first and second plurality of particlesmay comprise the same drug as described herein.

The coating may be any coating described herein. A preferred coating isethylcellulose.

The first and second drugs may be any of the drugs described herein thatone of skill in the art would combine for a therapeutic treatment (i.e.,a treatment comprising the combination of two different drugs). In apreferred embodiment, the first drug is hydrocodone and the second drugis chlorpheniramine

It is understood that the various aspects described in this and othersections may be combined. For example, the invention contemplates amethod for confirming the acceptability of quantity of drug-containingresin particles, where the drug-containing resin particles comprise afirst plurality of particles comprising hydrocodone and anethylcellulose coating, and a second plurality of uncoated particlescomprising a chlorpheniramine.

Methods of Preparing Suspensions with Desired Release Profiles

The invention also provides for a method of formulating liquid drugsuspensions. In one embodiment, the invention provides for a method offormulating a liquid drug suspension comprising suspending drug-containresin particles in a liquid suspension, wherein the drug-containingresin particles comprise a first plurality of particles comprising awater-permeable coating and a second plurality of uncoated particles,and wherein the first and second plurality of particles contain the samedrug. In a preferred embodiment, the liquid drug suspension provides anearly onset of therapeutic value, while masking the taste of the drugand maintaining bioequivalence and bioavailability.

The invention may provide an early onset of therapeutic value in whichat least 15% more of the drug will be released within the first 15, 30,60, 75, or 90 minutes of administration, as compared to conventionalforms of the same drug. Preferably substantially all of the earlyrelease of drug will occur in the gastric space, with only aninsignificant amount of drug released in the oral cavity, in order tomask the taste of the drug.

The coating may be any coating described herein. A preferred coating isethylcellulose. The drug may be any of the drugs described herein.

It is understood that the various aspects described in this and othersections may be combined.

Methods of Designing a Liquid Drug Suspension Formulation by RefiningDrug-Containing Resin Particles

In order to formulate a liquid drug suspension using drug-containingresin particles, it may be necessary to modify the particles to ensurethat the drug suspension is equivalent to a desired profile. As such,the invention provides for methods of designing liquid drug suspensionsby refining drug-containing resin particles.

In one embodiment, the invention provides for a method for designing aliquid dosage form comprising

(a) obtaining an initial preparation of drug-containing resin particles;

(b) combining a pre-determined amount of these initial drug-containingresin particles with a plurality of excipients in a container to form aninitial liquid drug suspension;

(c) introducing an aliquot of said initial drug suspension into adissolution medium after a pre-determined hold period, wherein saidpre-determined hold is substantially less than a period necessary for adrug suspension to fully age; and

(d) producing a test suspension in vitro dissolution profile bydetermining the concentration of drug in the dissolution medium at aseries of time points after the introduction of the test suspension,

(e) comparing said test suspension in vitro dissolution profile to acontrol in vitro dissolution profile obtained by performing an in vitrodissolution assay on a control liquid drug suspension, where the controlin vitro dissolution assay is performed after the same pre-determinedhold period. A suitable control liquid drug suspension would be onehaving a desired in vivo serum concentration profile observed in asubject who has been administered a finally formulated and fully agedsuspension product.

If the test suspension in vitro dissolution profile is not equivalent tothe control in vivo dissolution profile, then a new batch ofdrug-containing resin particles is prepared using a process modified asdescribed below, and the modified drug-containing resin particles arecombined with the plurality of excipients of step (b) to form a modifiedliquid drug suspension; and steps (c)-(e) are repeated until the invitro dissolution profile of said modified liquid drug suspension doesmatch the control in vitro dissolution profile.

Particle Size and Distribution

The method may comprise the step of modifying the particle size and/orsize distribution. It is beneficial to have a homogenous mixture ofparticles (i.e., less variance in particle size and a tighterdistribution of particle sizes) to maintain uniformity in a liquid drugsuspension. This may be achieved by passing the particles through ascreen or a series of screens, or by air classification or other fluidclassification. Large particles may contribute to a “gritty” mouthfeel,so it is preferred to have 80% or more of the particles below 200 μm indiameter. Smaller particles tend to provide a smoother product, but itmay be difficult to achieve small particle size without milling theparticles.

Coating Weight

The step of modifying may comprise increasing or decreasing the amountof the coating. For example, the step of modifying may compriseincreasing the weight of the coating to decrease the rate of dissolutionof the test suspension. Alternatively, the step of modifying maycomprise decreasing the weight of the coating to increase the rate ofdissolution of the test suspension.

Methods of increasing or decreasing the amount of the coating are knownin the art. See, e.g., U.S. Pat. Nos. 4,221,778 and 4,996,047; U.S.Publication Nos. 2006/0193877; 2007/0059270; 2007/01400983; and2007/0148239. The disclosure of each of these patents and publicationsis incorporated by reference herein in their entireties.

Drug Loading

The method may comprise modifying the amount of drug loaded onto theparticles. For example, the step of modifying may comprise increasingthe amount of drug loaded above the holding capacity of thedrug-containing resin particle to increase the rate of dissolution ofthe test suspension. (See U.S. Publication Nos. 2007/0059270;2007/01400983; and 2007/0148239). Alternatively, the step of modifyingmay comprise decreasing the amount of drug loaded below holding capacityon said drug-containing resin particle to decrease the rate ofdissolution of the test suspension.

Methods of modifying drug loading are known in the art. See, e.g., U.S.Pat. Nos. 4,221,778 and 4,996,047; U.S. Publication Nos. 2006/0193877;2007/0059270; 2007/01400983; and 2007/0148239. The disclosure of each ofthese patents and publications is incorporated by reference herein intheir entireties.

It is understood that the various aspects described in this and othersections may be combined (e.g., the methods may use any of thedissolution media described herein, the drug-containing resin particlesmay comprise a first plurality of particles comprising a first drug anda second plurality of particles comprising a second drug, etc.)

Methods of Formulating a Liquid Drug Suspension by Refining SuspensionParameters

In order to formulate a liquid drug suspension, it may be necessary tomodify the drug suspension to ensure that it is equivalent to a desiredprofile. As such, the invention provides for methods of formulatingliquid drug suspensions by refining the composition of the liquid drugsuspension and/or the procedure for its preparation.

In one embodiment, the invention provides for a method for formulating aliquid dosage form comprising

(a) obtaining drug-containing resin particles;

(b) combining a pre-determined amount of said drug-containing resinparticles with a plurality of excipients in a container to form aninitial liquid drug suspension;

(c) introducing an aliquot of said initial drug suspension into adissolution medium after a pre-determined hold period, wherein saidpre-determined hold is substantially less than a period necessary for adrug suspension to fully age;

(d) producing a test suspension in vitro dissolution profile bydetermining the concentration of drug in the dissolution medium at aseries of time points after said introduction; and

(e) comparing said test suspension in vitro dissolution profile to acontrol in vitro dissolution profile obtained by performing an in vitrodissolution assay on a control liquid drug suspension, wherein saidcontrol in vitro dissolution assay is performed after a pre-determinedhold period. A suitable control liquid drug suspension is one having adesired in vivo serum concentration profile observed in a subject whohas been administered a finally formulated and fully aged suspensionproduct.

If the test suspension in vitro dissolution profile is not equivalent tothe control in Diva dissolution profile, then a modified suspension isprepared using a process described below; and steps (c)-(e) are repeateduntil the in vitro dissolution profile of said modified liquid drugsuspension is equivalent to the control in vitro dissolution profile.

Ionic Salts

The method may comprise modifying the ionic strength or concentration ofthe initial liquid drug suspension. For example, the step of modifyingmay comprise increasing the ionic strength or concentration of theinitial liquid drug suspension which has been found to increase the rateof dissolution of the test suspension. Alternatively, the step ofmodifying may comprise decreasing the ionic strength or concentration ofthe initial liquid drug suspension which has been found to decrease therate of dissolution of the test suspension.

Methods of modifying ionic strength or concentration are disclosed inU.S. Publication No. 2009/0011027. The disclosure of this publication ishereby incorporated by reference in its entirety.

Active Resin-Site Balance

The method may comprise modifying the active resin-site balance of theinitial liquid drug suspension. For example, the step of modifying maycomprise changing the active resin-site balance to increase or decreasethe rate of dissolution of the test suspension. The rate of dissolutionmay be decreased by adding a pre-determined amount coated free resin tothe container (i.e., a coated particle that does not contain any drug).The rate of dissolution may also be decreased by adding a pre-determinedamount uncoated free resin to the container (i.e., an uncoated particlethat does not contain any drug).

Alternatively, the rate of dissolution may be increased by adding apre-determined amount of free drug to the container.

It is understood that the various aspects described in this and othersections may be combined (e.g., the methods may use any of thedissolution media described herein, the drug-containing resin particlesmay comprise a first plurality of particles comprising a first drug anda second plurality of particles comprising a second drug, etc.)

Suspensions and Methods of Preparing Suspensions Bioequivalent to aTarget Product

The invention provides for methods of making liquid drug suspensionsthat are bioequivalent to a target product. In some embodiments, variousparameters described herein may be adjusted such that the in vitrodissolution profile is equivalent to a desired profile of a targetproduct. In a preferred embodiment, the invention provides for a methodof making a liquid drug suspension that is bioequivalent to Tussionex®drug suspension using the methods described herein.

The invention also provides for extended release liquid drug suspensionsthat are bioequivalent to a target product. In one embodiment, theinvention provides a pharmaceutical composition comprising (a)hydrocodone adsorbed on ion-exchange polystirex to form coateddrug-resin particles; (b) chlorpheniramine adsorbed on ion-exchangepolystirex to form uncoated drug-resin particles; and (c) at least oneliquid carrier, where at least 50% the coated drug-resin particles arelarger than 50 μm. Preferably, at least 80% of the coated drug-resinparticles in this embodiment are smaller than 200 μm. In a preferredembodiment, the invention provides for an extended release liquid drugsuspension comprising hydrocodone polystirex and chlorpheniraminepolystirex that is bioequivalent to Tussionex® drug suspension.

The following examples describe various methods of obtaining dissolutionprofiles including a method of making a liquid drug suspension that isbioequivalent to Tussionex® drug suspension. These examples are notintended to limit the invention in any way.

Example 1 Dissolution Profile of Chlorpheniramine Polistirex DrugSubstance

The dissolution profiles of hydrocodone polistirex and chlorpheniraminepolistirex are considered. Hydrocodone polistirex resinate was preparedas described in U.S. Pub. Nos. 2007/0140983, 2007/0059270, and/or2007/0148239. Chlorpheniramine maleate is bound to polistirex cationexchange resin. The resin was polistirex IRP-69 from Rohm & Haas forboth drugs. A suspension containing both of these resinates insuspension was manufactured using the formula detailed in Table 1 andthe process detailed in Table 2.

TABLE 1 Test Formula Ingredient Ingredient Application Percent PurifiedWater, USP Hydration Agent 30.8% Ascorbic Acid pH Adjuster 0.03%Propylene Glycol, USP Solvent 3.33% Methylparaben Preservative 0.13%Propylparaben Preservative 0.04% Polysorbate 80 Surfactant 0.08% XanthanGum Thickener 0.5% Vegetable Oil Viscosity Agent 0.17% Liquid OrangeColor Colorant 0.002% D&C Yellow # 10 Colorant 0.002% Natural MangoFlavor Flavor 0.03% Uncoated Chlorpheniramine Active 0.59% PolistirexResin Coated Hydrocodone Active 1.0% Polistirex Resin Sucrose Sweetener12.5% High Fructose Corn Syrup Sweetener & 37.5% Viscosity AgentPurified Water, USP Diluent ≈13.2%

TABLE 2 Manufacturing Instructions Step Number Basic ManufacturingInstructions 1 Mix the Purified Water and Ascorbic Acid in the maincontainer. 2 Heat Propylene Glycol to ≈50° C. - add the Parabens,Polysorbate 80, and Xanthan Gum. 3 Add the Xanthan Gum/Paraben solutionto the main container and hydrate for 4 to 4.5 hours. 5 Add theVegetable Oil, Colors, and Flavor to the main container. 6 SprinkleChlorpheniramine and Hydrocodone Resin into the main container. 7 AddSucrose to the main container. 8 Add Corn Syrup to the main container. 9QS with Water.

Dissolution testing was performed on samples of the suspension preparedusing the protocol described above and stored for about 18 months.Samples of the suspension were pulled after mixing for 30 minutes andtested in USP Type II apparatus for dissolution testing (See FIGS. 4 and5). The apparatus contained 900 ml of 0.1N HCl, and pH was adjusted byadding various amounts of Potassium Phosphate Solution containing 0.5MPotassium Phosphate Monobasic and 1.2M Sodium Hydroxide.

To achieve a pH of 3.00, 72.6 mL of the Potassium Phosphate Solution wasadded.

To achieve a pH of 3.40, 75.7 mL of the Potassium Phosphate Solution wasadded.

To achieve a pH of 4.01, 77.0 mL of the Potassium Phosphate Solution wasadded.

To achieve a pH of 4.80, 77.8 mL of the Potassium Phosphate Solution wasadded.

To achieve a pH of 5.80, 80.9 mL of the Potassium Phosphate Solution wasadded.

To achieve a pH of 6.10, 82.9 mL of the Potassium Phosphate Solution wasadded.

These amounts were added to 900 ml of 0.1N HCl, and samples were pulledfor drug assay 90 minutes after the suspension was added.

These experimental results demonstrate that release of chlorpheniraminefrom polistirex resin is dependent upon the pH of the environment, whilerelease of hydrocodone is essentially pH-independent.

The chlorpheniramine polistirex drug substance does not include anysustained release coating system, yet it is still considered modifiedrelease. The mechanism of the drug release is purely pH and iondependent in practice. The extended release characteristics of the drugare created by the inability of the drug to become unbound from thepolistirex resin in an acidic environment (the stomach), while releasingin the higher pH environment of the gastrointestinal tract.

Chlorpheniramine also has a long biological half life in the body,between 12 and 43 hours in adults and 10 to 13 hours in children (seePhysician's Assistant's Drug Handbook, 2^(nd) Edition; SpringhousePublishing 2001), which aids in extending the effect of theantihistamine. The in-vivo data, depicted in FIG. 6, demonstrated theextended release nature of a suspension containing an uncoatedchlorpheniramine polistirex drug substance.

Example 2 Effect of Coating Level on Release Profile for HydrocodonePolistirex

Batches of ethylcellulose coated hydrocodone polistirex resinate wereprepared using three coating application iterations. Hydrocodonepolistirex resinate was prepared as described in U.S. Pub. Nos.2007/0140983, 2007/0059270, and/or 2007/0148239. The initial coatingapplication was stopped when the coating level reached an initial lowcoating level (weight per weight basis), the second coating applicationadded an additional coating to an intermediate coating level (medium),and the final application added an additional coating for a finalcoating level (high).

Separate suspensions of the coated hydrocodone resinates at each coatinglevel were prepared according to the protocol of Example 1. Samples ofeach suspension were pulled after two months in storage and tested inUSP Type II apparatus for dissolution testing. The dissolution mediainitially contained 900 mL of 0.1N HCl (i.e., pH of 1.2) for the firsthour. After the first hour, approximately 85 mL of potassiumphosphate/sodium hydroxide buffer was added to bring the pH up to ˜4.5,then after the second hour the pH is was finally brought up to ˜6.8 byadding approximately 15 mL of potassium phosphate/sodium hydroxidebuffer. The potassium phosphate/sodium hydroxide buffer is 0.5Mpotassium phosphate monobasic and 1.2M NaOH. The concentration at thefirst buffer addition is 0.04M potassium phosphate monobasic and 0.10MNaOH. The concentration at the final concentration is 0.05M potassiumphosphate monobasic and 0.12M NaOH. The sample was agitated at a 100rpm. The results of all three dissolution tests are presented in FIG. 7.

These results demonstrate the ability to significantly alter the releaseprofile of the coated hydrocodone resinate through additional coatingiterations, thereby exhibiting the primary release control mechanism.Using this coating iteration process, each batch of hydrocodone resinatecan be manufactured to the appropriate release level. Once the finalcoating has been completed, the finished coated hydrocodone resinate canbe tested for quality control and released for manufacturing of finalsuspension products.

The inventors concluded that the required coating level of coatedhydrocodone polistirex resin may vary slightly from batch to batch inorder to meet the required release specifications. This coating leveladjustment strategy, which will compensate for any slight differences inthe material or process used to manufacture the coated hydrocodonepolistirex resin, will produce a coated hydrocodone polistirex resinthat will consistently deliver a desired dissolution release profile.

Example 3 Dissolution Protocol Leading to In Vitro/In Vivo Correlation

A. Dissolution Results of Low Coating Level Hydrocodone Polistirex, HighCoating Level Hydrocodone Polistirex, and Tussionex® Pennkinetic® ERSuspension Hydrocodone Polistirex with the Proposed DissolutionProcedure

Hydrocodone coating levels that bracket the Reference Listed Drug (i.e.,Tussionex®) were determined by the results of in-vitro dissolutiontesting (as demonstrated in FIG. 8, which was a pilot batch).Suspensions utilizing hydrocodone resinate with a lower coating leveland a higher coating level were selected.

Tussionex® antitussive-antihistamine suspension contains hydrocodonepolistirex (sulfonated styrene-divinyl benzene copolymer) equivalent to10 mg hydrocodone bitartrate and chlorpheniramine polistirex equivalentto 8 mg chlorpheniramine maleate. To prepare a suspension that isbioequivalent, batches were manufactured using the formula detailed inTable 1 and the process detailed in Table 2 below and hydrocodonepolistirex and chlorpheniramine polistirex prepared as described inExamples 1 and 2. Two 100 Liter batches of the drug product weremanufactured: (i) Lot A using low coating level hydrocodone polistirexresin; and (ii) Lot B using high coating level hydrocodone polistirexresin.

TABLE 1 Test Formula Ingredient Ingredient Application Percent PurifiedWater, USP Hydration Agent 30.8% Ascorbic Acid pH Adjuster 0.03%Propylene Glycol, USP Solvent 3.33% Methylparaben Preservative 0.13%Propylparaben Preservative 0.04% Polysorbate 80 Surfactant 0.08% XanthanGum Thickener 0.5% Vegetable Oil Viscosity Agent 0.17% Liquid OrangeColor Colorant 0.002% D&C Yellow # 10 Colorant 0.002% Natural MangoFlavor Flavor 0.03% Uncoated Chlorpheniramine Active 0.59% PolistirexResin Coated Hydrocodone Active ≈1.0% Polistirex Resin (Lot A) or (LotB) Sucrose Sweetener 12.5% High Fructose Corn Syrup Sweetener & 37.5%Viscosity Agent Purified Water, USP Diluent ≈13.2%

TABLE 2 Manufacturing Instructions Step Number Basic ManufacturingInstructions 1 Mix the Purified Water and Ascorbic Acid in the maincontainer. 2 Heat Propylene Glycol to ≈50° C. - add the Parabens,Polysorbate 80, and Xanthan Gum. 3 Add the Xanthan Gum/Paraben solutionto the main container and hydrate for 4 to 4.5 hours. 5 Add theVegetable Oil, Colors, and Flavor to the main container. 6 SprinkleChlorpheniramine and Hydrocodone Resin into the main container. 7 AddSucrose to the main container. 8 Add Corn Syrup to the main container. 9QS with Water.

Dissolution testing was performed on these two batches using theprotocol described below and compared to Tussionex® drug suspension.

The dissolution methodology described herein is based on creating arobust in vitro dissolution test that will correlate with in vivostudies. For oral suspension formulations that contain coatedion-exchange resins suspended in a viscous liquid, dissolutionparameters were chosen as follows.

A known quantity of drug-containing liquid suspension is placed indissolution media which initially contains 900 mL of 0.1N HCl (i.e., pHof 1.2) for the first hour. After the first hour, approximately 85 mL of0.5M monobasic potassium phosphate and 1.2M NaOH is added to bring thepH up to 5.6 to 6.3, then after the second hour the pH is finallybrought up to ˜6.8 by adding approximately 15 mL of the potassiumphosphate/sodium hydroxide buffer. The dissolution procedure involvesapparatus II (paddles) agitating the sample at a 100 rpm.

Dissolutions are run at a fairly high rpm (75-100) due the viscosity ofthe suspension. The suspension dissolution profile was created bymimicking three pH parameters that are based upon ingestion pH ranges,and listed in Center for Drug Evaluation and Research (CDER) guidance asacceptable for multimedia dissolution tests. (See “Dissolution Testingof Immediate Release Solid Oral Dosage Forms—Appendix A” FDA, CDER,August 1997.)

The potassium salt is added to aid in the buffering of the solution at aconstant pH level and to supply cations to the media. These cations havebeen postulated to exchange with the bound drug and thereby causing achange in the dissolution profile, as compared to deionized water. (SeeU.S. Pat. No. 4,762,709, which is incorporated by reference herein inits entirety.)

2 mL portions are periodically taken from the medium (e.g., 30 minutes,1.5 hours and 3 hours, and optionally also 6, 8, and/or 12 hours). Thesamples are then filtered and analyzed with HPLC to find the percentdrug component released from the resinate into the surrounding medium.

The results of the dissolution assay are shown in FIGS. 9 and 10.

The coating level of the hydrocodone polistirex has an apparent effecton delaying the release of the drug through the semi-permeable membrane,which is evident by the faster release of the low coating level, ascompared to the high coating level. The Tussionex® release profile issimilar to the high level initially, but is slower to release over time.This profile could also be approximated by a combination of both resinsin varying amounts.

The chlorpheniramine polistirex release profiles are only pH dependent,as there is no coating on the resin, therefore these would bestatistically similar. After the three hour time point, when the pHadjustment has fully completed, the percent Relative Standard Deviation(% RSD) is less than 5%; after 6 hours all remaining time points the %RSD is less than 3%. This limit is within the method validationprotocols for spiked dissolution samples, therefore the release profileof chlorpheniramine in an in vitro situation of lots A and B isequivalent to Tussionex® drug suspension. Lots A and B provided an earlyonset of therapeutic value.

B. Clinical Results of Low Coating Level Hydrocodone Polistirex, HighCoating Level Hydrocodone Polistirex, and Tussionex® Pennkinetic® ERSuspension

A randomized three-way crossover, single-dose, open-label pilot study todetermine bioavailability of the low coating level hydrocodonepolistirex, high coating level hydrocodone polistirex, and Tussionex®drug suspension was conducted with twelve patients and followed thetesting and administration procedures of the relevant FDA guidances.(See “Bioavailability and Bioequivalence Studies for Orally AdministeredDrug Products—General Considerations”. FDA, Center for Drug Evaluationand Research (CDER); July, 2002; United States Pharmacopoeia. <1090>Statistical Procedures for Bioequivalence Studies Using a StandardTwo-Treatment Crossover Design, USP 30^(th) Edition).

Plasma samples were taken at regular intervals and analyzed for the twoactive pharmaceutical ingredients and the plasma concentrations wereplotted over time (see FIGS. 11 and 12).

The hydrocodone and chlorpheniramine plasma levels show a typicalbiological release profile. The clinical plasma concentration data,along with the dissolution release data in all four graphs can becorrelated to each other for a predicable in vitro-in vivo relationship.

C. Calculation of In Vitro-In Vivo Correlation of Coated HydrocodonePolistirex and Chlorpheniramine Polistirex, Based Upon Dissolution Dataand Clinical Plasma Data

To find a correlation between the dissolution results and the clinicalresults for Lot A, these results were plotted together and amathematical relationship was found. From the mean plasma concentrationdata from the clinical data, the area under the curve (AUC) as afunction of time using the trapezoidal rule¹ was determined, and alongwith the knowledge of the elimination rate constant (Kel), then thecalculation of Fa was possible². Fa, the fraction of the dose absorbedis as follows in Equation 1:

$F = \left( \frac{{Kel} \cdot V \cdot {AUC}}{Dose} \right)$with V being the Volume of the Dose (5 mL) and the “Dose” being 1×10⁷ ng(10 mg) for the equivalent of 10 mg of hydrocodone bitartrate. Thefraction of the dose was then converted into a cumulative percentagewhich was then plotted with the dissolution value. A Condition was thenderived from that graph, creating an in vitro-in vivo correlation, whichis shown in FIG. 13. ¹ Edwards & Penney, “Calculus and AnalyticalGeometry, 4^(th) Ed.” Prentice-Hall Inc. 1994.² Bourne, D. “A FirstCourse in Pharmacokinetics and Biopharinaceutics—Chapter 9”, Universityof Oklahoma, 2008.

Therefore, the relationship between the dissolution value andphysicochemical absorption rate was shown to be:

Equation 2—In Vitro-In Vivo Correlation of Hydrocodone:Y=3×10⁻⁷ e ^(0.1874x)

The correlation Coefficient value of 0.9877 shows a very goodcorrelation of the exponential and the actual data values.

Similarly the in vitro-in vivo correlation of Lot B and Tussionex® drugsuspension then becomes equation 3 and 4, respectively.

Equation 3—In Vitro-In Vivo Correlation of Hydrocodone in Lot B:Y=2×10⁻⁶ e ^(0.2641x)R ²=0.9823Equation 4—In Vitro-In Vivo Correlation of Hydrocodone in BrandedTussionex® Drug Suspension:Y=7×10⁻⁵ e ^(0.1969x)R ²=0.9833

For similar in vitro-in vivo correlation guidance published by theEnvironmental Protection Agency (EPA) for acute toxicity determination,³the R² that is cited of 0.775 is characterized as “shows a significantcomparability of data”. A successful correlation is published as havinga correlation coefficient >0.9⁴. Therefore, it was concluded that acorrelation coefficient of >0.98 is very promising for the coatedhydrocodone polistirex. ³ “Guidance Document on Using In vitro Data toEstimate In Vivo Starting Doses for Acute Toxicity”. InteragencyCoordinating Committee on the Validation of Alternative Methods and theNational Institute of Environmental Health Services; NIH Pub. No.01-4500; August, 2001.⁴ Polli, J. E. “IVIVR versus IVIVC”, Diss. Tech.Vol. 7, Issue 3; August 2000

The chlorpheniramine in vitro-in vivo correlations were lesspredictable, with R²<0.75 for Lot A and B, and only 0.88 for the brandedTussionex® drug suspension. This was not entirely unexpected. Thechlorpheniramine polistirex is considered an enterically immediaterelease dosage form, due to the pH dependent release mechanism of thedrug, as can be seen in FIG. 10 after the 1 hour pH addition. There isgenerally a low expectation for the IVIVC success for immediate releasedosages, and so it is not considered appropriate to use a correlation tocompare dissolution and clinical data sets.

Along with an IVIVC, other useful information may be obtained. Using theWager-Nelson method, the absorption rate constant (Ka) can be calculatedfor the coated hydrocodone polistirex, since Kel is known, and with thisconstant a pure mathematical model can be created for the plasmaabsorption of the specified dosage form, see equation 5 and FIG. 14.Therefore, a model can be used in creating a predictive mode forbioavailability and bioequivalence of future products.

Equation 5:Plasma Conc.=A[e ^(−kel*t) −e ^(−ka*t)]

Therefore, the plasma absorption concentration becomes the differencebetween the Kel rate and the Ka rate.

Conclusion

Although a non-linear IVIVC is fairly rare in literature, it is still agood predictor of a relationship between clinical and dissolution data.The correlation obtained according to the method of this invention isstill considered to meet the Level A regulatory guidance set forth bythe FDA. Therefore, the IVIVC described in this evaluation for coatedhydrocodone polistirex can serve as a surrogate for in vivabioavailability and possible support of biowaivers in future therapeuticproducts submitted for ANDAs and NDAs. These models can also assist inthe creation of future developmental dosages, scale-up and qualitycontrol changes throughout the manufacturing of the product life cycle.

Example 4 Time-Dependent Change in Release Behavior

It was noticed that when ethylcellulose coated hydrocodone polistirexresin was formulated in a Drug Product matrix as in Example 3, thedissolution profile of hydrocodone release changed over time. Thischange constituted an increase in the released amount of drug productover all dissolution time points. After about three to four weeks ofroom temperature storage, the release profile ceased shifting andremained stable over the remaining shelf-life of the Drug Product.Without wishing to be bound by theory, this phenomenon was theorized tobe a caused by changes in the coated hydrocodone polistirex resin withinthe Drug Product matrix to approach a thermodynamically stableequilibrium in the formulated suspension.

Coating levels of the hydrocodone polistirex resinate did not seem toappreciably affect the equilibrium shift of the release profile.Laboratory batches were made using the same two coating levelhydrocodone polistirex resinates that were used to manufacture thebatches used in Example 2. The change in the hydrocodone in-vitro drugrelease, as measured with the protocol described in Example 3, for bothlaboratory batches, regardless of the coating level, showed a similarequilibrium shift after various periods of storage at room temperature(FIGS. 15 and 16).

The equilibrium shift, from day 0 to day 30 at the 30 minute time pointwas 9.3% for the laboratory batch manufactured using the higher coatinglevel material and 9.9% for the laboratory batch manufactured using thelower coating level material. The equilibrium shift, from day 0 to day30 at the 8 hour time point was 2.0% for the laboratory batchmanufactured using the higher coating level material and 1.4% for thelaboratory batch manufactured using the lower coating level material.These amounts are very similar, with the difference in equivalence shiftbeing less than 1%, even though the dissolution release profiles aresignificantly different. FIGS. 15 and 16 demonstrate a graphicalrepresentation of changes in the Drug Products release profile over timemeasured from completion of final suspension with the two differentcoating levels described above.

A 300 Liter Pilot Batch hydrocodone equilibrium shift over the 28 dayequilibrium period (results in FIG. 17) was similar to the previouslyseen equilibrium shifts. The initial dissolution time point had a shiftof 8.5%, while the 6 hour time point resulted in a shift of 3.0%.

Example 5 Effect of Heating During Suspension Manufacture

Experiments were performed in an attempt to accelerate the equilibriumprocess. Product was prepared and stored as in Example 4 except that itwas manufactured at 50° C.

The first experiment performed in an attempt to accelerate theequilibrium process involved heating the Drug Product during themanufacturing process. This experiment was selected after reviewing FreeEnergy calculations and Gibbs Law⁵. Gibbs free energy AG is the workexchanged by the system with its surroundings, during a reversibletransformation of the system from some specified initial state to afinal state.ΔG=ΔH−TΔSwhere G is the Free Energy, H is the Standard Enthalpy, S is the Entropyof the system, and T is the Temperature of the system. ⁵ GeneralChemistry, Principles and Structures 3^(rd) Edition, J. E. Brandy and G.E. Humiston; John Wiley & Sons 1982.

If the ΔG becomes zero, then the system is at equilibrium. Due to thefact that the hydrocodone dissolution profile takes four weeks to reachequilibrium, the reaction would be considered non-spontaneous. Thisresults in a positive ΔG. Therefore, in order to decrease ΔG to zero,the term TΔS must be increased.

The heating of the Drug Product during manufacturing did not reduce theequilibrium time (results in FIG. 18). The final equilibrium resultsshowed an equilibrium shift of 10.1% for the first dissolution timepoint, decreasing to 2.0% for the final dissolution time point. This issimilar to previously seen equilibrium shifts over four weeks. As aresult of the heating, the final hydrocodone dissolution profile startedand ended with a higher release profile than the non-heated samples.

The conclusion from this is that heating during the manufacturingprocess may affect the resin coating, which may cause the hydrocodonerelease profile to deviate from the predetermined desired rate. Variousheating experiments involved heating batches at 40° C. and 50° C. aswell as additional periods of mixing at the end of the process followedby room temperature storage. All of these experiments resulted in thesame finding—the equilibrium time was not reduced.

Example 6 Effect of pH

Due to the ion exchange nature of the hydrocodone polistirex resin,different pH levels of the Drug Product were evaluated as a means ofaccelerating the equilibrium process. The first experiment was carriedout as described in Example 4 except for lowering the pH of the DrugProduct with an excess of Ascorbic Acid (results in FIG. 19). Theinitial dissolution time point had a shift of 9.5%, which is inaccordance with batches at the target pH of approximately 4.2. The finaldissolution time point at 8 hours had a shift of 16.6%, which was largerthan what was previously seen. This experiment included two otherbatches of Drug Product, one at the target pH and another that was madewithout Ascorbic Acid in order to achieve a high pH level. These batchesdemonstrated the same equilibrium shift as the batch manufactured withthe low pH.

All of these experiments resulted in the same finding—the equilibriumtime was not reduced, in fact the results were all very similar. The pHadjustments were made at the end of the process (as opposed to thebeginning of the process which is how this Drug Product is typicallyprepared).

Example 7 Effect of the Removal of Chlorpheniramine Polistirex Resin

A suspension containing only hydrocodone polistirex resin was preparedto determine whether the chlorpheniramine polistirex resin had an affecton the equilibrium shift of the hydrocodone dissolution release profile.This experiment was carried out as in Example 3 except for omittingchlorpheniramine polistirex resin. Results are shown in FIG. 20. Theinitial dissolution time point had a shift of 4.5%, which isapproximately half the value seen on similar batches. The finaldissolution time point at 8 hours had a shift of 2.7%, which is similarto previously seen shifts. This decrease in an equilibrium shift seemsto be due to the absence of chlorpheniramine polistirex resin. Thus, thepresence of polistirex resin which does not have bound hydrocodoneappears to affect the equilibrium shift. This result is consistent withthe need to determine release profiles using drug-resin particles whichare formulated in a suspension substantially similar to the finalformulation as defined herein in order to obtain an in vitro releaseprofile which can be used to predict the IVIVC of the final suspendedproduct.

Example 8 Profile Comparison of Particles Tested in the Final DrugSuspension

The invention provides for methods of characterizing drug-containingresin particles to determine if they meet particular quality parameters.The method includes the steps of suspending drug-containing resinparticles in a test suspension that is substantially similar inphysicochemical characteristics to a final drug suspension, such as thatdescribed in Example 3, and producing an in vitro dissolution profileobtained from the test suspension using a suitable dissolution protocol,such as that described in Example 3. Drug-containing resin particles maybe accepted or rejected based on this dissolution profile.

In this Example, release profiles of drug-containing resin particlestreated in different ways were compared using the protocol described inExample 3. In particular, the release profiles of hydrocodone resinshaving low and high coating weights were placed in a drug suspensiondescribed in Example 3, and aliquots of the drug suspension were assayedin the dissolution protocol of Example 3 after one day of storage. Theresulting profiles were compared with the release profiles ofhydrocodone resin particles having low and high coating weights thatwere not prepared in a drug suspension, but rather were introduceddirectly into the dissolution medium of Example 3 (i.e., as dry coatedparticles).

The top line in FIGS. 21 and 22 is the release profile of thehydrocodone resin when prepared in a drug suspension substantiallysimilar to a final drug suspension (“Suspension—Day 1”), and the lowerline is the release profile of the hydrocodone resin by itself, testedusing the same dissolution test methods as the finished product (samedissolution and HPLC settings), but without first suspending it in adrug suspension substantially similar to a final drug suspension. Thelower line of both figures shows a similar profile, indicating thatdissolution assays on dry particles are not sensitive to the differencesbetween the particle populations. On the other hand, after one day insuspension, the release profiles of the two population of particlesreflects the effect of coating weight expected from the results inExamples 2, 3, and 4.

This example demonstrates that the release profiles of liquid drugsuspensions comprising drug-resin particles may be used to evaluate therelease performance expected for loaded resin particles when prepared ina drug suspension substantially similar to a final drug suspension.However, if the loaded resin particles are tested directly, withoutformulation into a suspension, the release performance is changed. Usingthe method of this invention one can test the acceptability of adrug-containing resin particle without having to wait for a finalproduct to be formulated and fully aged, thereby saving time and expenseduring the production process. Of course, the release profile after oneday does not match the in vitro profile of a fully aged suspension, butthe profile after a preselected storage period can be correlated to thein vitro portion of an IVIVC for purposes of prediction.

Example 9 Modifying Particle Size and Distribution

Particle size is investigated in this Example by looking at twoparameters, particle size distribution and the actual particle size of acoated hydrocodone-containing resinate. Coated hydrocodone polistirex isthe only component assayed for drug release in this set of studies. Asthe chlorpheniramine polistirex release mechanism is purely ion and pHrelated (due to the lack of coating) release rate for chlorpheniramineis not expected to be dependent upon particle size.

Coated hydrocodone polistirex from a bulk sample was separated intovarious particle size ranges. A large 250 gram composite sample ofhydrocodone polistirex was sieved through six U.S. Standard Test Sieves.The percent weight distribution and percent assay equivalent tohydrocodone bitartrate that were determined are outlined in Table 3below as follows. The assay value of hydrocodone equivalent tohydrocodone bitartrate on a percent weight basis is fairly uniformthroughout the particles, with a relative variation of approximately 8%.As can be seen in the percent weight retained column, the majority ofthe sample has a particle size between 75 μm and 149 μm.

TABLE 3 Particle Size Separation and Analysis Hydrocodone Weight AssaySieve Size (Particle size) Retained (% w/w) USS 60 (>250 μm) 2.1% 15.2USS 80 (180 to 249 μm) 11.1% USS 100 (150 to 179 μm) 7.9% 16.1 USS 120(125 to 149 μm) 21.5% 16.2 USS 140 (106 to 124 μm) 20.7% 16.1 USS 200(75 to 105 μm) 22.3% 15.3 Pan Sample (<75 μm) 14.3% 15.0 Loss 0.1% —Total 100.0%

The percent volume of the composite sample (i.e., the product describedin Example 3 and referred to as “proposed product”), as measured usinglight scatter diffraction and displayed in FIG. 23 and Table 4 thatfollow, exhibited a similar distribution to the data obtained usingsieve analysis displayed in the Table 3 above.

TABLE 4 Particle size d0.1 Particle size d0.5 Particle size d0.9 [Thesize of the [The size of the [The size of the particle in micronsparticle in microns particle in below which 10% at which 50% of themicrons (on a volume sample is smaller below which basis) of the and 50%is 90% of the sample lies.] larger.] sample lies.] Reference  6 μm  22μm  95 μm Listed Drug Proposed 30 μm 100 μm 200 μm Product

The percent volume of each individual sample, as measured using lightscatter diffraction and displayed in the FIG. 24, also exhibited similardistribution to the data obtained using sieve analysis displayed in theTable 4 above.

This experiment shows that coated hydrocodone polistirex which producesrelease data bioequivalent to Tussionex® drug suspension may be preparedwith particle size distribution shifted toward larger particles (>50μm). Such particles may be used to prepare drug suspensions withoutrequiring milling of the resin particles. Dissolution studies indicatethat narrower ranges of particle size may be used to enhance releasecharacteristics. Suspensions with narrower ranges of particle size mayproduce more consistent release profiles.

All documents (e.g., patents and published patent applications)mentioned in this specification are hereby incorporated by reference intheir entirety.

The invention claimed is:
 1. A test method for characterizing how aliquid test drug suspension correlates to a controlled release liquidsuspension drug product suitable for commercial distribution comprising(a) obtaining drug-resin complex particles; (b) combining saiddrug-resin complex particles with a plurality of excipients in a liquidcarrier to form a liquid test drug suspension; (c) performing an invitro dissolution assay by introducing an aliquot of the liquid testdrug suspension into an in vitro dissolution medium to generate a testin vitro dissolution profile for the test drug suspension, wherein thereis a pre-determined hold period between the formation of said test drugsuspension and initiation of said dissolution assay for said test drugsuspension; and (d) comparing said test in vitro dissolution profile toa control in vitro dissolution profile generated by an in vitrodissolution assay for a control drug suspension, wherein there is apre-determined hold period between the formation of said control drugsuspension and initiation of said dissolution assay for said controldrug suspension, to determine whether the test in vitro dissolutionprofile matches the control in vitro dissolution profile, wherein thepre-determined hold period between the formation of said test drugsuspension and initiation of said dissolution assay for said test drugsuspension, and the pre-determined hold period between the formation ofsaid control drug suspension and initiation of said dissolution assayfor said control drug suspension are substantially identical and aresubstantially less than a period necessary for a drug suspension tobecome thermodynamically stable, and further wherein said control invitro dissolution profile correlates to a target in vivo profile of saidcontrolled release liquid suspension drug product.
 2. A test method forcharacterizing how a liquid test drug suspension correlates to acontrolled release liquid suspension drug product suitable forcommercial distribution comprising (a) obtaining drug-resin complexparticles; (b) combining said drug-resin complex particles with aplurality of excipients in a liquid carrier to form a liquid test drugsuspension; (c) performing an in vitro dissolution assay to generate atest in vitro dissolution profile for the test drug suspension, whereinsaid dissolution assay is initiated by introducing an aliquot of theliquid test drug suspension into an in vitro dissolution medium promptlyafter the formation of said test drug suspension; and (d) comparing saidtest in vitro dissolution profile to a control in vitro dissolutionprofile generated by a dissolution assay for a control drug suspension,wherein said dissolution assay for the control drug suspension isinitiated promptly after the formation of the control drug suspension,to determine whether the test in vitro dissolution profile matches thecontrol in vitro dissolution profile, wherein the dissolution assay ofthe test drug suspension and the dissolution assay of the control drugsuspension are initiated after substantially identical lag periods, andfurther wherein said control in vitro dissolution profile correlates toa target in vivo profile of said controlled release liquid suspensiondrug product.
 3. A method for determining the acceptability ofdrug-resin complex particles for use in a controlled release liquidsuspension drug suspension product suitable for commercial distribution,comprising (a) obtaining a sample of said drug-resin complex particles;(b) combining said sample with a plurality of excipients in a liquidcarrier to form a liquid test drug suspension; (c) performing an invitro dissolution assay by introducing an aliquot of the liquid testdrug suspension into an in vitro dissolution medium to generate a testin vitro dissolution profile for the test drug suspension, wherein thereis a pre-determined hold period between the formation of said test drugsuspension and the initiation of said dissolution assay for said testdrug suspension; (d) comparing said test in vitro dissolution profile toa control in vitro dissolution profile generated by an in vitrodissolution assay for a control drug suspension, wherein there is apre-determined hold period between the formation of said control drugsuspension and initiation of said dissolution assay for said controldrug suspension, to determine whether the test in vitro dissolutionprofile matches the control in vitro dissolution profile; (e) acceptingor rejecting said quantity of drug-resin complex particles based on thecomparison of step (d), wherein the pre-determined hold period betweenthe formation of said test drug suspension and initiation of saiddissolution assay for said test drug suspension, and the pre-determinedhold period between the formation of said control drug suspension andinitiation of said dissolution assay for said control drug suspensionare substantially identical and are substantially less than a periodnecessary for a drug suspension to become thermodynamically stable, andfurther wherein said control in vitro dissolution profile correlates toa target in vivo profile of said controlled release liquid suspensiondrug product.
 4. The method of claim 1, wherein if the test in vitrodissolution profile does not match the control in vitro dissolutionprofile, further comprising modifying the drug-resin complex particlesto form modified drug-resin complex particles and repeating steps(b)-(d) with said modified drug-resin complex particles.
 5. The methodof claim 1, wherein if the test in vitro dissolution profile does notmatch the control in vitro dissolution profile, further comprisingmodifying the test drug suspension to form a modified test drugsuspension and repeating steps (c)-(d) with said modified test drugsuspension.
 6. The method of claim 1, wherein said drug-resin complexparticles comprise a first plurality of particles comprising a firstdrug and a second plurality of particles comprising a second drug. 7.The method of claim 6, wherein said first plurality of particles furthercomprises a water-permeable coating.
 8. The method of claim 6, whereinthe first drug is hydrocodone and the second drug is chlorpheniramine.9. The method of claim 4, wherein said drug-resin complex particlescomprise a first and second plurality of particles, said first pluralityof particles containing a water-permeable coating, and further whereinsaid modifying comprises increasing the weight of said coating todecrease the rate of dissolution of the test suspension.
 10. The methodof claim 4, wherein modifying comprises modifying the size of thedrug-resin complex particle.
 11. The method of claim 4, wherein saidmodifying comprises increasing the amount of drug loaded above theholding capacity on said drug-resin complex particle to increase therate of dissolution of the test suspension.
 12. The method of claim 4,wherein said modifying comprises decreasing the amount of drug loadedbelow holding capacity on said drug-resin complex particle to increasethe rate of dissolution of the test suspension.
 13. The method of claim5, wherein said modifying comprises altering the ionic strength of saidtest drug suspension.
 14. The method of claim 5, wherein said modifyingcomprises altering the active resin-site balance of said test drugsuspension.
 15. The method of claim 1, wherein said dissolution mediuminitially has a pH of less than 2.0, and then is adjusted to a pH ofabove 6.0 about two hours after the introduction of said aliquot. 16.The method of claim 14, wherein said modifying comprises adding apre-determined amount of coated free resin to said container.
 17. Themethod of claim 14, wherein said modifying comprises adding apre-determined amount of uncoated free resin.
 18. The method of claim14, wherein said modifying comprises adding a pre-determined amount offree drug to said container.
 19. The method of claim 1, wherein saidpre-determined hold period is less than 48 hours.
 20. The method ofclaim 2, wherein the lag periods are less than one week.
 21. The methodof claim 1, wherein said test drug suspension is substantially similarin physicochemical characteristics to a finally formulated suspension.22. The method of claim 1, wherein said control drug suspension issubstantially similar in physicochemical characteristics to a finallyformulated suspension.
 23. The method of claim 1, wherein said test drugsuspension and said control drug suspension are substantially similar inphysicochemical characteristics to a finally formulated suspension. 24.The method of claim 2, wherein said test drug suspension issubstantially similar in physicochemical characteristics to a finallyformulated suspension.
 25. The method of claim 2, wherein said controldrug suspension is substantially similar in physicochemicalcharacteristics to a finally formulated suspension.
 26. The method ofclaim 2, wherein said test drug suspension and said control drugsuspension are substantially similar in physicochemical characteristicsto a finally formulated suspension.
 27. The method of claim 3, whereinsaid test drug suspension is substantially similar in physicochemicalcharacteristics to a finally formulated suspension.
 28. The method ofclaim 3, wherein said control drug suspension is substantially similarin physicochemical characteristics to a finally formulated suspension.29. The method of claim 3, wherein said test drug suspension and saidcontrol drug suspension are substantially similar in physicochemicalcharacteristics to a finally formulated suspension.
 30. The method ofclaim 1, where a portion of the drug-resin particles are coated with awater-permeable coating, and further wherein said test drug suspensionand said control drug suspension are substantially similar inphysicochemical characteristics to a finally formulated suspension. 31.The method of claim 2, where a portion of the drug-resin particles arecoated with a water-permeable coating, and further wherein said testdrug suspension and said control drug suspension are substantiallysimilar in physicochemical characteristics to a finally formulatedsuspension.
 32. The method of claim 3, where a portion of the drug-resinparticles are coated with a water-permeable coating, and further whereinsaid test drug suspension and said control drug suspension aresubstantially similar in physicochemical characteristics to a finallyformulated suspension.